JP2007530594A - Acrylonitrile derivatives for use in inflammation and immunity related applications - Google Patents

Abstract

【選択図】なしDisclosed is a new drug that overcomes one or more drawbacks of drugs commonly used in immunosuppression or in the treatment or prevention of inflammatory and autoimmune diseases.
A compound represented by the following structural formula: or a pharmaceutically acceptable salt, solvate or inclusion compound containing the compound. The variables of structural formula (I) are as described herein. The present invention meets the aforementioned need by providing some acrylonitrile that inhibits the production of IL-2. These compounds are particularly useful for immunosuppression and / or for treating or preventing inflammatory and immune diseases.

[Selection figure] None

Description

This patent application claims priority from US Provisional Patent Application No. 60 / 556,107 (filed Mar. 25, 2004), the entire contents of which are incorporated herein by reference.
(Field of Invention)
The present invention relates to chemical compounds having biological activity, ie vinyl cyanide derivatives, which can be used for immunosuppression, or for the treatment or prevention of inflammatory and immune diseases.

  Interleukin 2 (IL-2) acts on many cells involved in the immune system, including cytotoxic T cells, natural killer cells, activated B cells, and lymphokine activated cells. Is a T-cell-derived lymphokine that regulates It is a powerful T cell mitogen required for T cell proliferation and promotes progression from G1 to S in the cell cycle. This is a growth factor for all T lymphocyte subpopulations and stimulates natural killer cells (NK cells). It also acts as a growth factor for B cells and stimulates antibody production.

  Since it acts on both T and B cells, IL-2 serves as a central regulator in the immune response. That is, it plays a role in anti-inflammatory responses, tumor monitoring, and hematopoiesis. It also affects the production of other cytokines, including IL-2, tumor necrosis factor alpha (TNF-alpha) and TNF-beta secretion, and also stimulates the synthesis of interferon gamma (INF-gamma) in the periphery . Although IL-2 is useful for regulating the immune response as described above, it is also known to cause various problems. That is, IL-2 is known to damage the brain blood barrier and the cerebral vascular endothelium. These effects can cause neuropsychological side effects observed during the implementation of IL-2 therapy, such as fatigue, disorientation and depressive symptoms. Furthermore, it changes the electrophysiological response of nerve cells.

  T cells that cannot produce IL-2 become inactive (anergy: due to habituation). This may cause the T cells to become inactive against any antigenic stimulus that may be received in the future. In other words, agents that inhibit IL-2 production can be used for immunosuppression or to treat or prevent inflammation and immune diseases. This approach has been clinically demonstrated using immunosuppressive agents such as cyclosporine, FK506, and RS61443. However, despite this proof of concept, drugs that inhibit IL-2 production remain far from ideal. Among other problems, their administration has been hampered by their particularly limited effectiveness and the presence of undesirable side effects (dose-dependent nephrotoxicity and hypertension).

  Accordingly, there is a continuing need for new drugs that overcome one or more drawbacks inherent in drugs that are commonly used for immunosuppression or for the treatment or prevention of inflammatory and autoimmune diseases. Desirable new drugs, in particular, are effective against diseases or disorders that are currently untreatable or hardly treatable, have new mechanisms of action, can be used orally, and / or have reduced side effects. It is done.

  The present invention solves the above problems by providing certain acrylonitrile derivatives that inhibit IL-2 production. These compounds are particularly useful for immunosuppression and / or for treating or preventing inflammatory and immune diseases.

（ここで、Ｃｙ^１は単環式若しくは二環式の、芳香族若しくは非芳香族の、カルボシクリル若しくはヘテロシクリル化合物であり、
Ｙは単環式若しくは二環式の、芳香族若しくは非芳香族の、カルボシクリル若しくはヘテロシクリル基であり、
Ｒ^１は＝Ｏ、＝Ｓ、＝ＮＯＲ^４又は＝Ｃ（Ｒ^５）（Ｒ^５）であり、
Ｒ^２は単環式若しくは多環式の、非芳香族若しくは芳香族の、カルボシクリル若しくはヘテロシクリル基であり、Ｒ^１が＝ＯのときにはＲ^２が１つ以上のハロゲン、低級パーフルオロアルキル若しくは低級パーフルオロアルコキシで置換されたフェニル基であるか、又はＲ^１とＲ^２が統合して単環式若しくは多環式の、非芳香族若しくは芳香族の、カルボシクリル若しくはヘテロシクリル基を形成することが可能で、
個々のＲ^３はＣｙ^１に結合した置換基であり、独立してハロゲン、低級アルキル、低級ハロゲンアルキル、低級アルコキシ、低級ハロゲンアルコキシ、ＣＮ、ＮＯ_２、ＯＲ^４、Ｎ（Ｒ^４）（Ｒ^４）、ＳＲ^４、ＣＯ_２Ｒ^４、ＣＯＮ（Ｒ^４）（Ｒ^４）、ＳＯＲ^６、ＳＯ_２Ｒ^６、ＣＯＲ^４、ＮＲ^４ＣＯＲ^４、ＮＲ^４ＣＯＮ（Ｒ^４）（Ｒ^４）、ＳＯ_２Ｎ（Ｒ^４）（Ｒ^４）、ＮＲ^４ＳＯＲ^６及びＡｒ^２の中から選択され、
ｎは０，１，２又は３から選択される整数であり、
個々のＡｒ^２は独立してハロゲン、低級アルキル、低級ハロゲンアルキル、低級アルコキシ、低級ハロゲンアルコキシ、ＣＮ，ＮＯ_２，Ｒ^６，ＯＲ^４，Ｎ（Ｒ^４）（Ｒ^４），ＳＲ^４，ＣＯ_２Ｒ^４，ＣＯＮ（Ｒ^４）（Ｒ^４），ＳＯＲ^６，ＳＯ_２Ｒ^６，ＣＯＲ^４，ＮＲ^４ＣＯＲ^４，ＮＲ^４ＣＯＮ（Ｒ^４）（Ｒ^４），ＳＯ_２Ｎ（Ｒ^４）（Ｒ^４）又はＮＲ^４ＳＯＲ^６で任意に置換されたアリール又はヘテロアリール基であり、
個々のＲ^４は独立して水素、又は１つ以上のアミノ、アルキルアミノ、アルコキシ、アルキルチオ、オキソ（＝Ｏ）、チオ（＝Ｓ）、イミノ（＝ＮＨ）、アルキルイミノ（＝Ｎ−アルキル）、ハロゲン、アシル、ニトロ、ヒドロキシ、シアノ、アリール、アルキルアリール、アリールオキシ、アリールチオ、アリールアミノ、カルボシクリル、カルボシクリルオキシ、カルボシクリルチオ、カルボシクリルアミノ、ヘテロシクリル、ヘテロシクリルオキシ、ヘテロシクリルアミノ若しくはヘテロシクリルチオ基で任意に置換されたアルキル基であり、
個々のＲ^５は独立してＣＮ又はＣＯ_２Ｒ^４であり、及び
個々のＲ^６は独立して１つ以上のアミノ、アルキルアミノ、アルコキシ、アルキルチオ、オキソ（＝Ｏ）、チオ（＝Ｓ）、イミノ（＝ＮＨ）、アルキルイミノ（＝Ｎ−アルキル）、ハロゲン、アシル、ニトロ、ヒドロキシ、シアノ、アリール、アルキルアリール、アリールオキシ、アリールチオ、アリールアミノ、カルボシクリル、カルボシクリルオキシ、カルボシクリルチオ、カルボシクリルアミノ、ヘテロシクリル、ヘテロシクリルオキシ、ヘテロシクリルアミノ又はヘテロシクリルチオ基で任意に置換されたアルキル基である。） The present invention relates to a compound having the following structural formula (I) or a pharmaceutically acceptable salt, solvate or inclusion compound containing the compound.

(Where Cy ¹ is a monocyclic or bicyclic aromatic or non-aromatic carbocyclyl or heterocyclyl compound;
Y is a monocyclic or bicyclic, aromatic or non-aromatic carbocyclyl or heterocyclyl group;
R ¹ is = O, = S, = NOR ⁴ or = C (R ⁵ ) (R ⁵ ),
R ² is a monocyclic or polycyclic, non-aromatic or aromatic carbocyclyl or heterocyclyl group, and when R ¹ is ═O, R ² is one or more halogen, lower perfluoroalkyl or lower perfluoro group. It is a phenyl group substituted with fluoroalkoxy, or R ¹ and R ² can be combined to form a monocyclic or polycyclic, non-aromatic or aromatic carbocyclyl or heterocyclyl group. ,
Each R ³ is a substituent bonded to Cy ¹ and is independently halogen, lower alkyl, lower halogen alkyl, lower alkoxy, lower halogen alkoxy, CN, NO ₂ , OR ⁴ , N (R ⁴ ) (R ⁴ ), SR ⁴ , CO ₂ R ⁴ , CON (R ⁴ ) (R ⁴ ), SOR ⁶ , SO ₂ R ⁶ , COR ⁴ , NR ⁴ COR ⁴ , NR ⁴ CON (R ⁴ ) (R ⁴ ), SO ₂ Selected from N (R ⁴ ) (R ⁴ ), NR ⁴ SOR ⁶ and Ar ² ;
n is an integer selected from 0, 1, 2 or 3;
Each Ar ² is independently halogen, lower alkyl, lower halogen alkyl, lower alkoxy, lower halogen alkoxy, CN, NO ₂ , R ⁶ , OR ⁴ , N (R ⁴ ) (R ⁴ ), SR ⁴ , CO _2. R ⁴ , CON (R ⁴ ) (R ⁴ ), SOR ⁶ , SO ₂ R ⁶ , COR ⁴ , NR ⁴ COR ⁴ , NR ⁴ CON (R ⁴ ) (R ⁴ ), SO ₂ N (R ⁴ ) (R ⁴ ) or an aryl or heteroaryl group optionally substituted with NR ⁴ SOR ⁶ ;
Each R ⁴ is independently hydrogen, or one or more amino, alkylamino, alkoxy, alkylthio, oxo (═O), thio (═S), imino (═NH), alkylimino (═N-alkyl) , Halogen, acyl, nitro, hydroxy, cyano, aryl, alkylaryl, aryloxy, arylthio, arylamino, carbocyclyl, carbocyclyloxy, carbocyclylthio, carbocyclylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino or heterocyclylthio An alkyl group optionally substituted with a group,
Each R ⁵ is independently CN or CO ₂ R ⁴ , and each R ⁶ is independently one or more amino, alkylamino, alkoxy, alkylthio, oxo (═O), thio (═S) , Imino (= NH), alkylimino (= N-alkyl), halogen, acyl, nitro, hydroxy, cyano, aryl, alkylaryl, aryloxy, arylthio, arylamino, carbocyclyl, carbocyclyloxy, carbocyclylthio, An alkyl group optionally substituted with a carbocyclylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino or heterocyclylthio group. )

  The present invention further includes a pharmaceutical composition comprising an effective amount of the disclosed compound or a pharmaceutically acceptable salt, solvate or inclusion compound comprising the same, or an effective amount of a compound disclosed herein. To inhibit IL-2 production in vivo or in vitro using the product. All the methods of the present invention can be carried out with the compounds disclosed herein alone or in combination with other drugs such as immunosuppressants, anti-inflammatory agents or drugs for immune diseases.

(Definition)
Unless otherwise stated, the terms used in this specification are defined as follows.
In the present specification, the terms “aromatic ring” and “aryl” (alone or as part of other terms such as alkylaryl, aryloxy, arylamino group, etc.) are monocyclics composed of carbon atoms and hydrogen atoms. Represents a formula or polycyclic aromatic ring or ring group. Examples of suitable aryl groups include fused carbocyclic moieties of benzene rings such as phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, naphthyl groups, and 5,6,7,8, -tetrahydronaphthyl groups. However, it is not limited to these. An aryl group is unsubstituted or substituted with one or more conventional aryl substituents (preferably lower alkyl or alkyl substituted with one or more halogens), hydroxy, alkoxy (preferably lower alkoxy), alkylthio, cyano, Substitution with halogen, amino and nitro groups is also possible. Preferably, the aryl group is a monocyclic ring consisting of 6 carbon atoms.

  As used herein, the term “carbocyclyl” (alone or as part of another term such as a carbocyclyloxy, carbocyclylthio, carbocyclylamino group, etc.) is a monocyclic composed of carbon and hydrogen atoms. Represents an aromatic or non-aromatic ring, or a cyclic group thereof, of formula or polycyclic. Examples of suitable carbocyclyl groups include phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, naphthyl, fused carbocyclic moieties of benzene rings such as 5,6,7,8, -tetrahydronaphthyl, cycloalkyl, cyclo Examples include, but are not limited to, alkenyl, bicycloalkyl, and bicycloalkenyl groups. A carbocyclyl group is unsubstituted or substituted with one or more conventional aryl substituents, including but not limited to alkyl (preferably lower alkyl or alkyl substituted with one or more halogens), hydroxy, alkoxy (preferably lower (Including alkoxyl), alkylthio, cyano, halogen, amino, and nitro groups). Preferably the carbocyclyl group is a monocyclic ring consisting of 6 carbon atoms.

  As used herein, the term “alkyl” (alone or as part of another term, for example, alkylaryl, alkylamino, alkylthio, alkyloxy, etc.) has 1 to 10 carbon atoms, saturated Represents a linear or branched acyclic hydrocarbon. Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl, As saturated branched alkyl, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-di Tylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl -3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3- Examples include diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl group and the like. The alkyl group contained in the compound of the present invention is amino, alkylamino, alkoxy, alkylthio, oxo, halogen, acyl, nitro, hydroxy, cyano, aryl, alkylaryl, aryloxy, arylthio, arylamino, carbocyclyl, carbocyclyl. It may be optionally substituted with one or more commonly used alkyl substituents such as oxy, carbocyclylthio, carbocyclylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylthio groups, and the like. In addition, carbon atoms in the alkyl moiety, particularly carbon atoms inside the alkyl moiety, are replaced with carbonyl (C═O), thiocarbonyl (C═S), oxygen (O), sulfur (S), or nitrogen (N). You may do it. As the compound of the present invention, use of a lower alkyl group is particularly preferred.

  As used herein, the term “alkenyl” (alone or as part of another term) refers to an alkyl group having in particular 2 to 10 carbon atoms and having at least one carbon-carbon double bond. To express. Exemplary linear and branched alkenyls include vinyl, aryl, 1-butyl, 2-butenyl, isobutenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 1-octynyl, 2-octynyl, 3-octynyl, 1-noninyl, 2-noninyl, 3-noninyl, 1-decynyl, 2-decynyl 3-decynyl group and the like can be mentioned.

  As used herein, the term “alkynyl” (alone or as part of another term) represents an alkyl group, particularly having from 2 to 10 carbon atoms and having at least one carbon-carbon triple bond. . Representative straight chain and branched alkynyl include acetinyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 4-pentynyl, 1-hexynyl, 2- Examples include hexynyl, 5-hexynyl, 1-heptynyl, 1-noninyl, 2-noninyl, 8-noninyl, 1-decynyl, and 2-decynyl groups.

  As used herein, the term “cycloalkyl” (alone or as part of another term) particularly represents a saturated cyclic alkyl group having from 3 to 10 carbon atoms. Exemplary cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl groups.

  As used herein, the term “bicycloalkyl” (alone or as part of another term) specifically refers to a bicyclic alkyl having 8 to 14 carbon atoms and at least one saturated cyclic alkyl ring. Represents. Representative bicycloalkyls include indanyl, 1,2,3,4-tetrahydronaphthyl, 5,6,7,8-tetrahydronaphthyl, perhydronaphthyl groups, and the like.

  As used herein, the term “cycloalkenyl” (alone or as part of another term) has at least one carbon-carbon double bond in the cyclic system, especially 5 to 10 A cyclic non-aromatic alkyl group having a carbon atom is represented. Typical cycloalkenyls include cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctenyl, cyclooctadienyl, cyclooctatetraenyl, cyclononenyl, cysteinyl Clononadienyl, cyclodecenyl, cyclodecadienyl group and the like can be mentioned.

  As used herein, the term “heterocycle” or “heterocyclyl” (alone or as part of another term) refers to either saturated non-aromatic, unsaturated non-aromatic, saturated aromatic or unsaturated aromatic. Represents a ring of a monocyclic or bicyclic heterocyclic compound (particularly having 3 to 10 members). A 3-membered heterocycle may contain up to 3 heteroatoms, and a 4- to 10-membered heterocycle may contain up to 4 heteroatoms. Individual heteroatoms are independently selected from nitrogen, which can be quaternized; oxygen; and sulfur, including sulfoxides and sulfones. Heterocycles may be bonded to different atoms or carbon atoms. Typical heterocycles include pyridine, furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl, indolizinyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, morpholinyl, pyrrolidinyl, pyrrolidinyl, piperidinyl, piperidinyl, Examples include benzo [1,3] dioxolyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl groups. Naturally, saturated heterocycle groups fused with a benzene ring such as 1,2,3,4-tetrahydroquinoline are also included in this definition. The heteroatom may be a protecting group known to those skilled in the art, such as hydrogen bonded to nitrogen replaced with a tert-butoxycarbonyl group. Furthermore, the ring of the heterocyclic compound may optionally be substituted with one or more conventional heterocyclic compound ring substituents (but not limited to, a halogen atom, an alkyl group, or an aryl group). Of such substituted heterocyclic groups, only stable isomers are included in this definition.

  As used herein, the term “heteroaromatic” or “heteroaryl” (alone or as part of another term) refers to a member ring of carbon atoms and one or more heteroatom ring members (eg, Monocyclic or polycyclic heteroaromatic ring (or a ring group thereof) composed of (such as oxygen, sulfur or nitrogen). In one embodiment, the heteroaromatic ring is selected from 5-8 membered heteroaryl rings. In another embodiment, the heteroaromatic ring is a 5- or 6-membered heteroaryl ring. Representative heteroaryls include furyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, indolizinyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, triazolyl, thiadiazolyl, benzofuryl, benzothienyl, indolyl, isoindolyl, benzoxazolyl, benzil Examples include imidazolyl, benzothiazolyl, isoxazolyl, indazolyl, benzisothiazolyl, benzopyrazinyl, benzotriazolyl, benzothiadiazolyl, quinolyl, isoquinolyl, quinazolyl, phthalazolyl, cinnolyl and the like. These heteroaryl groups (indolizinyl by itself) are optionally (but are not limited to) amino, alkylamino, alkoxy, alkylthio, oxo, halogen, acyl, nitro, hydroxyl, cyano, aryl, alkylaryl, aryloxy Substituted with one or more known heteroaryl substituents, including arylthio, arylamino, carbocyclyl, carbocyclyloxy, carbocyclylthio, carbocyclylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylthio groups, etc. May be. Individual heteroaryl substituents include halogen and lower alkyl groups optionally substituted with one or more halogens.

  As used herein, the term “halogen” or “halo” (alone or as part of another term) represents —F, —Cl, —Br, or I.

  In this specification, the terms “subject”, “patient”, and “animal” are used interchangeably, eg, cow, monkey, horse, sheep, pig, bird (such as chicken, turkey, quail, etc.). , Cats, dogs, mice, rats, rabbits, guinea pigs and humans. These terms include mammals and non-mammals. A preferred subject, patient or animal is a mammal, preferably a human.

  As used herein, the term “lower” refers to a group having up to 4 atoms. For example, “lower alkyl” represents an alkyl group having 1 to 4 carbon atoms, and “lower alkenyl” or “lower alkynyl” represents an alkenyl or alkynyl group having 2 to 4 carbon atoms, respectively. Particularly preferred are lower substituents.

  When a plurality of individual substituents are present in a certain structure or portion, the identity of these substituents is independent in each case, and those substituents in the certain structure or portion are different from each other. May be the same or different. In particular, a combination or description of individual substituents and other substituents described in each specific example and representative compound of the present invention is preferable, and it is clearly stated or disclosed that a combination of such substituents is preferable. Even if it is not done, its interpretation remains the same.

  The compounds of the invention are defined herein by chemical structure and / or chemical name. When a compound is represented by both a chemical structure and a chemical name, or when the chemical structure and the chemical name contradict each other, the chemical structure takes precedence in identifying the compound. Only those substituents and variable symbols foreseen by the present invention are selected and combined that result in a stable compound. As used herein, the term “stable” is consistent with the ability to produce the compound and for the purposes detailed herein (eg, therapeutic or prophylactic administration to a subject). Period represents a state in which the compound is maintained in a certain state. In particular, these compounds are stable at temperatures below 40 ° C. for at least one week, avoiding excessive moisture. Making such selections and combinations is easy for those skilled in the art and can be determined without undue experimentation.

  In this specification, the term “pharmaceutically acceptable salt” is a salt formed from a basic group and an acid contained in a certain compound disclosed in the present invention. Such salts include sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acidic phosphate, isonicotinate, lactic acid Salt, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, glucone Acid salt, glucaronate, sulphonate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (ie, 1 , 1-methylene-bis- (2-hydroxy-3-naphthoate)). Alternatively, the term “pharmaceutically acceptable salt” is prepared from an acidic functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base contained in the disclosed compounds. Represents a modified salt. Suitable bases include alkali metal hydroxides such as sodium, potassium and lithium; alkaline earth metal hydroxides such as calcium and magnesium; hydroxides of other metals such as aluminum and zinc Ammonia and organic amines such as mono-, di-, or trialkylamines that are unsubstituted or substituted with hydroxyl groups; dicyclohexylamine; tributylamine; pyridine; N-methyl, N-ethylamine; diethylamine; Mono-bis-, or tris- (2-hydroxyethyl) amine, such as mono-bis-, or tris- (2-hydroxyethyl) amine, 2-hydroxy-tert-butylamine, or tris- (hydroxymethyl) methylamine Lower alkylamines), N, N-dimethyl-N- ( N, N-di-lower alkyl-N- (hydroxy lower alkyl) -amines such as -hydroxyethyl) amine or tri- (2-hydroxyethyl) amine; N-methyl-D-glucamine; and arginine, lysine However, it is not limited to these.

  As used herein, the term “pharmaceutically acceptable solvate” refers to a solvate produced by the association of one or more solvent molecules with one of the disclosed compounds. . The term solvate includes hydrates (eg, monohydrate, dihydrate, trihydrate, tetrahydrate, etc.).

  As used herein, the term “asthma” refers to pulmonary disease, a disorder or disease characterized by reversible airway obstruction, airway inflammation, and increased airway responsiveness to various stimuli.

  “Immunosuppression” refers to a disorder of the components of the immune system that results in reduced immune function. This disorder can be measured by conventional methods, including whole blood examination of lymphocyte function, confirmation of lymphocyte proliferation and evaluation of T cell surface antigen expression. The anti-sheep red blood cell (SRBC) primary (IgM) antibody response assay (usually called the plaque assay) is one specific method. For this and other methods, see Luster, M. et al. I. , Portier, C, Pait, D.M. G. , White, K .; L. , Jr. , Gennings, C, Munson, A .; E. , And Rosenthal, G .; J. et al. (1992) “Risk Assessment in Immunotoxicology 1: Sensitivity and the Predictability of Immunity Tests” Fundam. Appl. Toxicol. 18, 200-210. In addition, T cell-dependent immunogens are also particularly useful assays (Dean, JH, House, RV, and Luster, MI (2001) “Immunotoxicology: Effects of, and Responses to , Drugs and Chemicals "Principles and Methods of Toxology: 4th edition (edited by A. W. Hayes), pp. 1415-1450, Taylor & Francis, Philadelphia, Pennsylvania).

  The compounds of the present invention can be used for the treatment of subjects suffering from immune diseases. As used herein, the term “immune disease” refers to a disease or the like (disease, modulation, or symptom) caused by an animal's immune system, including autoimmune diseases. Immune diseases include diseases that involve abnormalities in immune components (diseases, modulation, or symptoms), and diseases that substantially or completely involve the immune system. An autoimmune disease is a disease in which the animal's own immune system mistakenly attacks the animal itself, thereby targeting the body's own cells, tissues, and / or organs. For example, the autoimmune reaction adversely affects the brain in multiple sclerosis and the intestine in Crohn's disease. In other autoimmune diseases such as systemic lupus erythematosus (SLE), the affected tissues and organs differ between individual patients with the same disease. Patients with SLE have skin and joint damage, while other patients have skin, kidney and lung damage. Ultimately, damage to some tissues by the immune system may be as permanent as by destruction of pancreatic insulin-producing cells in type 1 diabetes. Individual autoimmune diseases that can be ameliorated using the compounds and methods of the present invention include, but are not limited to, autoimmune diseases of the nervous system (eg, multiple sclerosis, myasthenia gravis, Guillain). Autoimmune neuropathies such as Valley syndrome and autoimmune uveitis), blood autoimmune diseases (eg, autoimmune hemolytic anemia, pernicious anemia, and autoimmune thrombocytopenia), vascular self Immune diseases (eg, temporal arteritis, antiphospholipid antibody syndrome, vasculitis such as Wegener's granulomatosis, and Behcet's disease), autoimmune diseases of the skin (eg, psoriasis, herpetic dermatitis, vulgaris) Pustular and vitiligo), gastrointestinal autoimmune diseases (eg, Crohn's disease, ulcerative colitis, primary biliary cirrhosis, and autoimmune hepatitis), endocrine gland autoimmune diseases (eg, type 1 or Diabetes, including diabetes, Graves' disease, Hashimoto's thyroiditis, autoimmune ovitis and testicular inflammation, and adrenal autoimmune diseases); multi-organ autoimmune diseases (including connective tissue and musculoskeletal diseases) (eg Rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, spondyloarthropathy such as ankylosing spondylitis, and Sjogren's syndrome). In addition, diseases involving other immune systems such as graft-versus-host disease and allergic diseases are also included in the definition of immune diseases herein. Since many immune diseases are caused by inflammation, there are some overlapping diseases between diseases considered immune diseases and inflammatory diseases. In view of the purpose of the present invention, it is desirable to consider that in the case of such overlapping diseases, it is either an immune disease or an inflammatory disease. As used herein, “treatment of an immune disease” refers to an immune disease, a symptom of the disease, or the It represents administration of a compound of the present invention to a subject having a predisposition to such a disease.

  As used herein, the term “allergic disease” refers to a disease or the like (disease, modulation, or symptom) associated with an allergic reaction to a normally harmless substance. These substances may be found in the environment (such as indoor air pollutants and air allergens), and some are found outside the environment (substances that cause dermatological or food allergies) like). Allergens can enter the body via various routes such as inhalation, food intake, skin contact or injection (including by insect stings). Many allergic diseases are associated with atopy, a predisposition to produce allergic antibody IgE. IgE increases the susceptibility of mast cells everywhere in the body, so in atopic patients, disease often appears in more than one organ. In the present invention, allergic diseases include hypersensitivity caused by re-exposure to a sensitizing allergen and causing release of inflammatory mediators. Allergic diseases include, but are not limited to, allergic rhinitis (eg hay fever), sinusitis, rhinosinusitis, chronic or recurrent otitis media, drug reaction, insect sting reaction, latex reaction, conjunctivitis, urticaria, Includes anaphylaxis and anaphylaxis-like reactions, atopic dermatitis, asthma and food allergies.

  The compounds of the present invention can be used for the prevention or treatment of subjects with inflammatory diseases. As used herein, the term “inflammatory disease” refers to a disease or the like (disease, modulation, or symptom) characterized by inflammation of a living tissue. These include local inflammatory responses and systemic inflammation. Examples of such inflammatory diseases include: transplant rejection, such as graft rejection or transplanted Langerhans rejection in diabetic subjects; arthritis, rheumatoid arthritis, osteoarthritis And chronic inflammatory diseases of the joint, including bone diseases with increased bone resorption; inflammatory bowel diseases such as ileitis, ulcerative colitis, Barrett syndrome, and Crohn's disease; asthma, adult dyspnea, and chronic Inflammatory pulmonary diseases such as obstructive airway disease; inflammatory diseases of the eye including corneal dystrophy, trachoma, rotiferous disease, uveitis, sympathetic ophthalmitis and endophthalmitis; gingivitis and periodontitis Chronic inflammatory diseases of the gums including: tuberculosis; leprosy; complications of uremia, renal inflammatory diseases including glomerulonephritis and nephrosis; inflammatory diseases of the skin including sclerosing dermatitis, psoriasis and eczema ;God Chronic demyelinating disease, multiple sclerosis, AIDS-induced neurodegeneration and Alzheimer's disease, infectious meningitis, encephalomyelitis, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis and viral Or inflammatory diseases of the central nervous system, including autoimmune encephalitis; autoimmune diseases, immune complex vasculitis, systemic lupus and lupus erythematosus; systemic lupus erythematosus (SLE); and heart disease such as cardiomyopathy Inflammatory disease, ischemic heart disease, hypercholesterolemia, atherosclerosis; and various other diseases due to important inflammatory components including pre-eclampsia; chronic liver failure, brain and spinal cord trauma, cancer. Alternatively, systemic, such as Gram positive or Gram negative bacterial shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to proinflammatory cytokines (eg shock associated with proinflammatory cytokines) Sexual inflammation is also included. Such shocks may be induced by chemotherapeutic agents used, for example, in cancer chemotherapy. In the present specification, “treatment of inflammatory disease” refers to treatment of an inflammatory disease, its symptoms, or its predisposition to a subject having an inflammatory disease, symptoms of such diseases, or its predisposition. Represents administration of a compound of the present invention for the purpose of reducing, altering, affecting or preventing.

  The compounds of the invention can also be used to treat subjects in need of immunosuppression, such as subjects who have undergone skin grafting or organ transplantation (diabetic subjects who have undergone transplantation of the islets of Langerhans).

“Effective amount” refers to either the amount of a compound that results in an effective outcome when the compound is administered to a subject, or the amount of a compound that provides the desired pharmacological activity in vivo and in vitro. In cases of inflammatory and autoimmune diseases, effective outcomes of clinical symptoms include reduced severity or severity and / or longevity of symptoms associated with the disease or modulation compared to no treatment. Includes extending and / or improving the quality of life of the subject. The exact amount of compound administered to a subject will be determined by the type and severity of the disease, disorder or condition, and the characteristics of the subject such as health, age, sex, weight and drug resistance. It also depends on the severity and type of inflammatory or autoimmune disease, or the degree of immunosuppression required. One skilled in the art can determine the appropriate dose as determined by these and other factors. Effective amounts of the disclosed compounds range particularly from about 1 mg / mm ² per day to about 10 g / mm ² per day, preferably from 10 mg / mm ² to about 1 g / mm ² per day.

  Since the compounds of the present invention contain one or more chiral centers and / or double bonds, such as double bond isomers (ie, geometric isomers), enantiomers, or diastereomers It may exist as a stereoisomer. For compounds described by structure or name in this specification, unless the stereochemical characteristics of individual atoms are specifically stated, all enantiomers and stereoisomers of the corresponding compounds are included, i.e., pure as stereoisomers. Includes only isomers (geometrically pure, enantiomerically pure, or diastereomerically pure) as well as mixtures of enantiomers and stereoisomers.

  Terms such as “inhibit IL-2 production” refer to inhibiting IL-2 synthesis (eg, by inhibiting transcription (mRNA expression) or translation (protein expression)) and / or IL−. Inhibiting IL-2 secretion of cells having the ability to produce and / or secrete 2 (eg, T lymphocytes).

  In the present specification, a composition that “significantly” contains a compound means that the composition is about 80% by weight or more, more preferably about 90% by weight or more, still more preferably about 95% by weight or more, and most preferably, Represents about 97% by weight or more.

  In the present specification, a composition that is “substantially free of a compound” means that the composition is about 20% by weight or less, more preferably about 10% by weight or less, still more preferably about 5% by weight or less, Most preferably, it represents about 3% by weight or less.

  In the present specification, the reaction is “significantly completed” means that the target product is about 80% by weight or more, more preferably the target product is about 90% by weight or more, and still more preferably the target product is about It represents 95% by weight or more, and most preferably contains about 97% by weight or more of the desired product.

  As used herein, a “racemic mixture” refers to a state in which the corresponding enantiomer is about 50% relative to about 50% of the enantiomer in relation to all chiral centers in the molecule. The present invention includes any pure enantiomers, high purity enantiomers, pure diastereomers, high purity diastereomers, and racemic mixtures of the disclosed compositions.

  Mixtures of enantiomers and diastereomers can be obtained by known methods such as chiral phase gas chromatography, chiral phase high performance liquid chromatography, crystallization of compounds as chiral salt complexes, or crystallization of compounds in chiral solvents. Can be separated into component enantiomers or stereoisomers. Also, enantiomers and diastereomers can be prepared by known asymmetric synthesis methods using intermediates, reagents and catalysts that are pure as diastereomers or pure as enantiomers.

  The compounds of the invention are defined herein by chemical structure and / or chemical name. If a compound is described with a chemical structure and / or chemical name, and if the chemical structure and chemical name conflict, the chemical structure takes precedence in identifying the compound.

  When a compound of the present invention is administered to a patient, for example veterinary to a non-human animal, or for amelioration of livestock disease, or clinically to a human, eg in isolated form Or as an isolated form in a pharmaceutical composition. As used herein, “isolated” means that the compound of the invention is (a) a natural source, such as a plant or cell, preferably a cultured bacterial cell, or (b) a synthetic organic chemical reaction mixture. Denotes being separated from any other component. Preferably, the compounds of the invention are purified by conventional methods. In the present specification, “purified” means that, when isolated, the compound of the present invention contained in the isolate contains at least 95% by weight, preferably at least 98% by weight. .

  Only the choice and combination of substituents that result in a stable structure is a problem. Such selection and combination is obvious to those skilled in the art and can be determined without undue experimentation.

  The invention may be more fully understood by reference to the following detailed description and examples, which are merely illustrative of the embodiments of the invention and are not intended to limit the invention in any way. Absent.

(Specific embodiment)
The present invention relates to compounds and pharmaceutical compositions particularly useful for immunosuppression, or for treating or preventing inflammatory and immune diseases.

  Specific methods and pharmaceutical compositions of the present invention include a compound disclosed as an active ingredient.

  One embodiment of the present invention relates to a method of immunosuppressing a patient, or a method of treating or preventing an inflammatory disease or immune disorder comprising administering an effective amount of a compound disclosed herein.

Ｃｙ^１は単環式若しくは二環式の、芳香族若しくは非芳香族の、カルボシクリル若しくはヘテロシクリル化合物であり、
Ｙは単環式若しくは二環式の、芳香族若しくは非芳香族の、カルボシクリル若しくはヘテロシクリル基であり、
Ｒ^１は＝Ｏ、＝Ｓ、＝ＮＯＲ^４又は＝Ｃ（Ｒ^５）（Ｒ^５）であり、
Ｒ^２は単環式若しくは多環式の、非芳香族若しくは芳香族の、カルボシクリル若しくはヘテロシクリル基であり、Ｒ^１が＝ＯのときにはＲ^２が１つ以上のハロゲン、低級パーフルオロアルキル若しくは低級パーフルオロアルコキシで置換されたフェニル基であるか、又はＲ^１とＲ^２が統合して単環式若しくは多環式の、非芳香族若しくは芳香族の、カルボシクリル若しくはヘテロシクリル基を形成することが可能で、
個々のＲ^３はＣｙ^１に結合した置換基であり、独立してハロゲン、低級アルキル、低級ハロゲンアルキル、低級アルコキシ、低級ハロゲンアルコキシ、ＣＮ、ＮＯ_２、ＯＲ^４、Ｎ（Ｒ^４）（Ｒ^４）、ＳＲ^４、ＣＯ_２Ｒ^４、ＣＯＮ（Ｒ^４）（Ｒ^４）、ＳＯＲ^６、ＳＯ_２Ｒ^６、ＣＯＲ^４、ＮＲ^４ＣＯＲ^４、ＮＲ^４ＣＯＮ（Ｒ^４）（Ｒ^４）、ＳＯ_２Ｎ（Ｒ^４）（Ｒ^４）、ＮＲ^４ＳＯＲ^６及びＡｒ^２の中から選択され、
ｎは０，１，２又は３から選択される整数であり、
個々のＡｒ^２は独立してハロゲン、低級アルキル、低級ハロゲンアルキル、低級アルコキシ、低級ハロゲンアルコキシ、ＣＮ，ＮＯ_２，Ｒ^６，ＯＲ^４，Ｎ（Ｒ^４）（Ｒ^４），ＳＲ^４，ＣＯ_２Ｒ^４，ＣＯＮ（Ｒ^４）（Ｒ^４），ＳＯＲ^６，ＳＯ_２Ｒ^６，ＣＯＲ^４，ＮＲ^４ＣＯＲ^４，ＮＲ^４ＣＯＮ（Ｒ^４）（Ｒ^４），ＳＯ_２Ｎ（Ｒ^４）（Ｒ^４）又はＮＲ^４ＳＯＲ^６で任意に置換されたアリール又はヘテロアリール基であり、
個々のＲ^４は独立して水素、又は１つ以上のアミノ、アルキルアミノ、アルコキシ、アルキルチオ、オキソ（＝Ｏ）、チオ（＝Ｓ）、イミノ（＝ＮＨ）、アルキルイミノ（＝Ｎ−アルキル）、ハロゲン、アシル、ニトロ、ヒドロキシ、シアノ、アリール、アルキルアリール、アリールオキシ、アリールチオ、アリールアミノ、カルボシクリル、カルボシクリルオキシ、カルボシクリルチオ、カルボシクリルアミノ、ヘテロシクリル、ヘテロシクリルオキシ、ヘテロシクリルアミノ若しくはヘテロシクリルチオ基で任意に置換されたアルキル基であり、
個々のＲ^５は独立してＣＮ又はＣＯ_２Ｒ^４であり、及び
個々のＲ^６は独立して１つ以上のアミノ、アルキルアミノ、アルコキシ、アルキルチオ、オキソ（＝Ｏ）、チオ（＝Ｓ）、イミノ（＝ＮＨ）、アルキルイミノ（＝Ｎ−アルキル）、ハロゲン、アシル、ニトロ、ヒドロキシ、シアノ、アリール、アルキルアリール、アリールオキシ、アリールチオ、アリールアミノ、カルボシクリル、カルボシクリルオキシ、カルボシクリルチオ、カルボシクリルアミノ、ヘテロシクリル、ヘテロシクリルオキシ、ヘテロシクリルアミノ又はヘテロシクリルチオ基で任意に置換されたアルキル基である。 One embodiment of the present invention is a compound represented by the following structural formula (I), or a pharmaceutically acceptable salt, solvate or inclusion compound containing the compound. here:

Cy ¹ is a monocyclic or bicyclic, aromatic or non-aromatic carbocyclyl or heterocyclyl compound;
Y is a monocyclic or bicyclic, aromatic or non-aromatic carbocyclyl or heterocyclyl group;
R ¹ is = O, = S, = NOR ⁴ or = C (R ⁵ ) (R ⁵ ),
R ² is a monocyclic or polycyclic, non-aromatic or aromatic carbocyclyl or heterocyclyl group, and when R ¹ is ═O, R ² is one or more halogen, lower perfluoroalkyl or lower perfluoro group. It is a phenyl group substituted with fluoroalkoxy, or R ¹ and R ² can be combined to form a monocyclic or polycyclic, non-aromatic or aromatic carbocyclyl or heterocyclyl group. ,
Each R ³ is a substituent bonded to Cy ¹ and is independently halogen, lower alkyl, lower halogen alkyl, lower alkoxy, lower halogen alkoxy, CN, NO ₂ , OR ⁴ , N (R ⁴ ) (R ⁴ ), SR ⁴ , CO ₂ R ⁴ , CON (R ⁴ ) (R ⁴ ), SOR ⁶ , SO ₂ R ⁶ , COR ⁴ , NR ⁴ COR ⁴ , NR ⁴ CON (R ⁴ ) (R ⁴ ), SO ₂ Selected from N (R ⁴ ) (R ⁴ ), NR ⁴ SOR ⁶ and Ar ² ;
n is an integer selected from 0, 1, 2 or 3;
Each Ar ² is independently halogen, lower alkyl, lower halogen alkyl, lower alkoxy, lower halogen alkoxy, CN, NO ₂ , R ⁶ , OR ⁴ , N (R ⁴ ) (R ⁴ ), SR ⁴ , CO _2. R ⁴ , CON (R ⁴ ) (R ⁴ ), SOR ⁶ , SO ₂ R ⁶ , COR ⁴ , NR ⁴ COR ⁴ , NR ⁴ CON (R ⁴ ) (R ⁴ ), SO ₂ N (R ⁴ ) (R ⁴ ) or an aryl or heteroaryl group optionally substituted with NR ⁴ SOR ⁶ ;
Each R ⁴ is independently hydrogen, or one or more amino, alkylamino, alkoxy, alkylthio, oxo (═O), thio (═S), imino (═NH), alkylimino (═N-alkyl) , Halogen, acyl, nitro, hydroxy, cyano, aryl, alkylaryl, aryloxy, arylthio, arylamino, carbocyclyl, carbocyclyloxy, carbocyclylthio, carbocyclylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino or heterocyclylthio An alkyl group optionally substituted with a group,
Each R ⁵ is independently CN or CO ₂ R ⁴ , and each R ⁶ is independently one or more amino, alkylamino, alkoxy, alkylthio, oxo (═O), thio (═S) , Imino (= NH), alkylimino (= N-alkyl), halogen, acyl, nitro, hydroxy, cyano, aryl, alkylaryl, aryloxy, arylthio, arylamino, carbocyclyl, carbocyclyloxy, carbocyclylthio, An alkyl group optionally substituted with a carbocyclylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino or heterocyclylthio group.

Another embodiment of the present invention is represented by Structural Formula (I). here:
Cy ¹ is phenyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, tetrazolyl, optionally fused with benzene, pyridine, pyrimidine, triazine, tetrazine, furan, thiophene, pyrrole, oxazole, imidazole, thiazole, isoxazole, pyrazole or isothiazole, Furyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiazolyl or thiadiazolyl group,
A compound.
The remaining variables in the structural formula (I) are the same as described above.

個々の構造式（Ｉ）から（ＸＩＩ）は、ベンゼン、ピリジン、ピリミジン、トリアジン、テトラジン、フラン、チオフェン、ピロール、オキサゾール、イミダゾール、チアゾール、イソキサゾール、ピラゾール又はイソチアゾールで任意に融合され、
ＺはＯ、Ｓ又はＮＲ^４であり、及び
個々のＸは独立してＣＨ、ＣＲ^３又はＮである。
残りの変数は前記と同様である。 Another embodiment of the present invention is a compound represented by Structural Formula (I). here:
Cy ¹ is a group of the following structural formula (II), (III), (IV), (V), (VI), (VII), (VIII), (X), (XI), or (XII) And

The individual structural formulas (I) to (XII) are optionally fused with benzene, pyridine, pyrimidine, triazine, tetrazine, furan, thiophene, pyrrole, oxazole, imidazole, thiazole, isoxazole, pyrazole or isothiazole,
Z is O, S or NR ⁴ and each X is independently CH, CR ³ or N.
The remaining variables are the same as described above.

Ｒ^１は＝Ｏ、＝Ｓ、＝ＮＯＲ^４又は＝Ｃ（Ｒ^５）_２であり、Ｒ^２はアリール、シクロアルキル、ビシクロアルキル、シクロアルケニル、ビシクロアルケニル又はヘテロシクリル基であり、Ｒ^１が＝Ｏである場合にはＲ^２が１つ以上のハロゲン、低級パーフルオロアルキル若しくは低級パーフルオロアルコキシ基で置換されたフェニル基であるか、又はＲ^１とＲ^２が統合されアリール、シクロアルキル、ビシクロアルキル、シクロアルケニル、ビシクロアルケニル又はヘテロシクリル基を形成する。
好ましくは、Ｒ^１とＲ^２が統合されアリール、シクロアルキル、ビシクロアルキル、シクロアルケニル、ビシクロアルケニル又はヘテロシクリル基を形成する。
更に好ましくは、Ｒ^１とＲ^２が統合され、任意に１つ以上のハロゲン、低級パーフルオロアルキル若しくは低級パーフルオロアルコキシ基で置換されたフェニル基、更に好ましくは同様に置換された１，４−フェニル基を形成する。
構造式（ＸＩＩＩ）の残りの変数は、前記の構造式（Ｉ）について記載したものと同様である。 Another embodiment of the present invention is a compound represented by the following structural formula (XIII), or a pharmaceutically acceptable salt, solvate or inclusion compound containing the compound. here:

R ¹ is ═O, ═S, ═NOR ⁴ or ═C (R ⁵ ) ₂ , R ² is an aryl, cycloalkyl, bicycloalkyl, cycloalkenyl, bicycloalkenyl or heterocyclyl group, and R ¹ is ═O R ² is a phenyl group substituted with one or more halogen, lower perfluoroalkyl or lower perfluoroalkoxy groups, or R ¹ and R ² are combined to form aryl, cycloalkyl, bicycloalkyl. Forms a cycloalkenyl, bicycloalkenyl or heterocyclyl group.
Preferably R ¹ and R ² are combined to form an aryl, cycloalkyl, bicycloalkyl, cycloalkenyl, bicycloalkenyl or heterocyclyl group.
More preferably, R ¹ and R ² are combined and optionally substituted with one or more halogen, lower perfluoroalkyl or lower perfluoroalkoxy groups, more preferably 1,4-substituted Form a phenyl group.
The remaining variables of structural formula (XIII) are the same as those described for structural formula (I) above.

Another example is a compound represented by the structural formula (XIII), in which R ² is C═O, and the remaining variables are the same as described above.

ＱはＣＨ又はＮ、好ましくはＣＨである。
環Ａは任意にいずれかの置換可能な炭素原子の位置で置換され、任意に置換されたフェニル環に任意に融合される。
Ｒ^１は＝Ｏ、＝Ｓ、＝ＮＯＲ^４又は＝Ｃ（Ｒ^５）（Ｒ^５）である。
Ｒ^２は単環式若しくは多環式の、非芳香族若しくは芳香族の、カルボシクリル若しくはヘテロシクリル化合物である；若しくは統合されたＲ^１とＲ^２が単環式若しくは多環式の、非芳香族若しくは芳香族の、カルボシクリル若しくはヘテロシクリル化合物基を生成する可能性がある；好ましくは、Ｒ^１が＝Ｏである場合、Ｒ^２が１つ以上のハロゲン、低級パーフルオロアルキル若しくは低級パーフルオロアルコキシ基で置換されたフェニル基である。
構造式（ＸＩＶ）の残りの変数は、構造式（Ｉ）について記載したものと同様である。 Another embodiment of the present invention is a compound represented by the following structural formula (XIV), or a pharmaceutically acceptable salt, solvate or inclusion compound of this compound. here:

Q is CH or N, preferably CH.
Ring A is optionally substituted at any substitutable carbon atom position and is optionally fused to an optionally substituted phenyl ring.
R ¹ is ═O, ═S, ═NOR ⁴ or ═C (R ⁵ ) (R ⁵ ).
R ² is a monocyclic or polycyclic, non-aromatic or aromatic carbocyclyl or heterocyclyl compound; or the combined R ¹ and R ² are monocyclic or polycyclic, non-aromatic or May produce an aromatic, carbocyclyl or heterocyclyl compound group; preferably, when R ¹ is ═O, R ² is substituted with one or more halogen, lower perfluoroalkyl or lower perfluoroalkoxy groups Phenyl group.
The remaining variables in structural formula (XIV) are the same as those described for structural formula (I).

Another embodiment of the present invention is a compound represented by the structural formula (XIV). here:
Cy ¹ is phenyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, tetrazolyl optionally fused with benzene, pyridine, pyrimidine, triazine, tetrazine, furan, thiophene, pyrrole, oxazole, imidazole, thiazole, isoxazole, pyrazole or isothiazole groups. , Furyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiazolyl, or thiadiazolyl group.
The remaining variables of structural formula (XIV) are the same as described above.

Another embodiment of the present invention is a compound represented by the structural formula (XIV). here:
Cy ¹ is a group of structural formula (II), (III), (IV), (V), (VI), (VII), (VIII), (X), (XI), or (XII) . The remaining variables of structural formula (XIV) are the same as described above.

構造式（ＸＶ）及び（ＸＶＩ）の残りの変数は構造式（ＸＩＶ）について先に記載したものと同様である。好ましくは、構造式（ＸＶ）において、Ｒ^１とＲ^２が統合され任意に置換されたアリール（好ましくはフェニル）であり；構造式（ＸＶＩ）において、Ｒ^２は任意に置換されたフェニルである。更に好ましくは、Ｒ^１とＲ^２（構造式（ＸＶ）において）及びＲ^２（構造式（ＸＶＩ）において）で表されたアリール基（好ましくはフェニル環）から生成されたＡ環及びアリール基（好ましくはフェニル環）は、任意にそして独立してハロゲン、低級アルキル、低級ハロゲンアルキル（好ましくは低級パーフルオロアルキル）、低級アルコキシ、低級ハロゲンアルコキシ基（好ましくは低級パーフルオロアルコキシ）、ＣＮ，ＮＯ_２，Ｒ^６，ＯＲ^４，Ｎ（Ｒ^４）（Ｒ^４），ＳＲ^４，ＣＯ_２Ｒ^４，ＣＯＮ（Ｒ^４）（Ｒ^４），ＳＯＲ^６，ＳＯ_２Ｒ^６，ＣＯＲ^４，ＮＲ^４ＣＯＲ^４，ＮＲ^４ＣＯＮ（Ｒ^４）（Ｒ^４），ＳＯ_２Ｎ（Ｒ^４）（Ｒ^４），及びＮＲ^４ＳＯＲ^６から独立して選択された１つ以上の基で置換される。 Another embodiment of the present invention is a compound represented by the following structural formula (XV) or (XVI). here:

The remaining variables in structural formulas (XV) and (XVI) are the same as described above for structural formula (XIV). Preferably, in Structural Formula (XV), R ¹ and R ² are combined and optionally substituted aryl (preferably phenyl); in Structural Formula (XVI), R ² is optionally substituted phenyl . More preferably, an A ring and an aryl group formed from an aryl group (preferably a phenyl ring) represented by R ¹ and R ² (in the structural formula (XV)) and R ² (in the structural formula (XVI)) ( Preferably the phenyl ring is optionally and independently halogen, lower alkyl, lower halogen alkyl (preferably lower perfluoroalkyl), lower alkoxy, lower halogen alkoxy groups (preferably lower perfluoroalkoxy), CN, NO ₂ , R ⁶ , OR ⁴ , N (R ⁴ ) (R ⁴ ), SR ⁴ , CO ₂ R ⁴ , CON (R ⁴ ) (R ⁴ ), SOR ⁶ , SO ₂ R ⁶ , COR ⁴ , NR ⁴ COR ⁴ , NR ⁴ CON (R ⁴ ) (R ⁴ ), SO ₂ N (R ⁴ ) (R ⁴ ), and one or more groups independently selected from NR ⁴ SOR ⁶ Is done.

Ｒ^１０とＲ^１１は独立してＨ、低級アルキル、低級ハロゲンアルキル、フラニル、チエニル、フェニル、低級アルコキシ又は低級ハロゲンアルコキシであり、またＲ^３は個々に−Ｈ、低級アルキル、低級ハロゲンアルキル、低級アルコキシ又は低級ハロゲンアルコキシであり；構造式（ＸＶＩＩ）及び（ＸＶＩＩＩ）の残りの変数は構造式（ＸＶ）と（ＸＶＩ）について先に記載したものと同様である。更に好ましくは、Ｒ^３は独立して、−Ｈ、低級アルキル、低級ハロゲンアルキル、低級アルコキシ又は低級ハロゲンアルコキシであり、Ｒ^１とＲ^２（構造式（ＸＶＩＩ）において）及びＲ^２（構造式（ＸＶＩＩＩ）において）で表されたアリール基（好ましくはフェニル環）から生成されたアリール基（好ましくはフェニル環）は、１つ以上のハロゲン、低級パーフルオロアルキル、低級パーフルオロアルコキシ基で置換される；そして、Ｒ^１０とＲ^１１は独立してＨ、低級アルキル、低級パーフルオロアルキルである。 More preferably, the compound of the present invention is represented by the structural formula (XVII) or (XVIII). here:

R ¹⁰ and R ¹¹ are independently H, lower alkyl, lower halogen alkyl, furanyl, thienyl, phenyl, lower alkoxy or lower halogen alkoxy, and R ³ is individually —H, lower alkyl, lower halogen alkyl, lower Alkoxy or lower halogen alkoxy; the remaining variables in structural formulas (XVII) and (XVIII) are the same as described above for structural formulas (XV) and (XVI). More preferably, R ³ is independently —H, lower alkyl, lower halogen alkyl, lower alkoxy or lower halogen alkoxy, and R ¹ and R ² (in structural formula (XVII)) and R ² (structural formula ( An aryl group (preferably a phenyl ring) formed by an aryl group (preferably a phenyl ring) represented by XVIII) is substituted with one or more halogen, lower perfluoroalkyl, lower perfluoroalkoxy groups And R ¹⁰ and R ¹¹ are independently H, lower alkyl, or lower perfluoroalkyl.

  Other embodiments of the invention include pharmaceutical compositions comprising an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate or inclusion compound thereof. . This pharmaceutical composition is useful for immunosuppression or for treating or preventing inflammatory and immune diseases.

  Further examples of the present invention include effective amounts of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate or inclusion compound thereof, or Includes a method of suppressing the immune system in a subject in need of immunosuppression comprising administering to the subject a disclosed compound, or a pharmaceutical composition comprising a pharmaceutically acceptable salt, solvate or inclusion compound of the compound. It is. In general, a physician or veterinarian can determine whether a subject requires immunosuppression. In particular, immunosuppression is necessary for subjects who have undergone organ transplantation. In other examples, immunosuppression against subjects with autoimmune or inflammatory diseases may be required.

  Further examples of the present invention include effective amounts of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate or inclusion compound thereof, or A method of immunosuppression or inflammatory disease comprising administering a disclosed compound, or a pharmaceutical composition comprising a pharmaceutically acceptable salt, solvate or inclusion compound thereof to a patient in need thereof And methods for treating or preventing immune disorders.

  Still other examples include an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate or inclusion compound thereof, or disclosed herein. And methods of inhibiting IL-2 production using a pharmaceutical composition comprising a prepared compound, or a pharmaceutically acceptable salt, solvate or inclusion compound thereof.

  The substituents used for the compounds of structural formula (I) or any of the individual compounds shown below can be used in any combination that results in the formation of a stable compound. Any such combination is included in the present invention.

  Representative compounds of the present invention are listed in the table shown in Example 2.

  The invention is further defined by reference to the following examples describing in detail the pharmaceutical compositions of the compounds of the invention. It will be apparent to those skilled in the art that various modifications, in materials and methods, can be made without departing from the purpose and significance of the invention. The following examples are provided to aid the understanding of the present invention and should not be construed as limiting the invention described and claimed herein. Substitution of the present invention for any equivalent within the scope of those skilled in the art, now known and later known, as well as changes in pharmaceutical composition or minor changes in experimental design are described herein. Should be considered within the scope of the present invention.

(Method of treatment and prevention)
In accordance with the present invention, an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate or inclusion compound thereof, or a compound disclosed herein, Or a pharmaceutical composition comprising a pharmaceutically acceptable salt of the compound, a solvate or an inclusion compound for a patient in need of immunosuppression, or a patient in need of treating or preventing inflammatory diseases and immune diseases. Be administered.

  The responsiveness of an individual inflammatory disease or immune disease in a subject can also be measured directly (after administration of a compound or pharmaceutical composition of the invention, inflammatory cytokines (such as IL-2, IFN-γ, etc.)) Can be inferred based on the fact that the cause and progress of the disease have been elucidated. The disclosed compounds, or pharmaceutically acceptable salts, solvates or inclusion compounds thereof, can be assayed for the desired therapeutic or prophylactic pharmacological activity in vitro or in vivo prior to administration to humans. For example, known animal models of inflammatory or immune diseases can be used to demonstrate the safety and efficacy of the compounds of the present invention.

(Pharmaceutical composition and dosage form)
The pharmaceutical compositions and dosage forms of the present invention comprise a corresponding amount of one or more active ingredients to immunosuppress a given pharmaceutical composition or dosage form, or treat or prevent inflammatory diseases and immune disorders Formulated in an administrable manner. Preferred pharmaceutical compositions and dosage forms comprise a disclosed compound, or a pharmaceutically acceptable salt, solvate or inclusion compound thereof, optionally in combination with one or more other active ingredients.

  The unitary dosage form of the present invention can be administered to a patient by oral, transmucosal (eg, nasal, sublingual, vaginal, buccal, rectal) or parenteral (eg, subcutaneous, intravenous, bolus administration). Suitable for injection, intramucosal or intraarterial) or transdermal administration. Examples of dosage forms include, but are not limited to, tablets, caplets, capsules such as soft capsules with elasticity, cachets, troches, lozenges, dispersions, suppositories, ointments, poultices, pasta preparations, powders , Coatings, creams, hardeners, solutions, patches, aerosols (eg nasal spray or inhalation), gels, suspensions (eg aqueous or non-aqueous liquid suspensions, O / W emulsions, or W) / O liquid emulsions), solutions, and liquid dosage forms suitable for oral or transmucosal administration to patients, liquid dosage forms suitable for parenteral administration to patients, and non-patients to patients Sterile solid pharmaceutical compositions (eg, crystalline or amorphous solids) that can be dissolved to provide a liquid dosage form suitable for oral administration are included.

  The composition, shape, and type of dosage form of the present invention will vary, particularly depending on their method of administration. For example, a dosage form suitable for transmucosal administration would contain a smaller amount of active ingredient compared to an oral dosage form used to treat the same indication. This feature of the invention will be readily apparent to those skilled in the art.

  Exemplary pharmaceutical compositions and dosage forms comprise one or more additives. Suitable additives are well known to those skilled in the pharmaceutical arts and include, but are not limited to, examples of suitable additives described herein. Whether an individual additive is suitable for inclusion in a pharmaceutical composition or dosage form includes, but is not limited to, a variety of well-known to those skilled in the art, including methods that may be administered to a patient. It depends on various factors. For example, oral dosage forms such as tablets may contain additives that are not suitable for administration in parenteral dosage forms.

  The suitability of an individual additive can depend on the individual active ingredients of the dosage form. For example, degradation of some active ingredients may be accelerated by some additives such as lactose or when exposed to water. Active ingredients that include primary or secondary amines (eg, N-desmethylvenlafaxine and N, N-didesmethylvenlafaxine) are individually susceptible to such accelerated degradation. Accordingly, the present invention includes pharmaceutical compositions and dosage forms that contain little, if any, lactose. As used herein, the term “free of lactose” is used to significantly increase the degradation rate of the active ingredient, even if the amount of lactose contained is included. Indicates insufficient. The lactose-free pharmaceutical compositions of the present invention are well known to those skilled in the art and may include, for example, additives listed in the United States Pharmacopeia (USP) SP (XXI) / NF (XVI) . Pharmaceutical compositions that are generally free of lactose include pharmaceutical compositionally compatible and pharmaceutically acceptable amounts of active ingredients, binders / excipients, and lubricants. Preferred lactose-free dosage forms include active ingredients, microcrystalline cellulose, non-gelatinized starch, and magnesium stearate.

  The present invention further includes dry pharmaceutical compositions and dosage forms that contain active ingredients because water promotes the degradation of some compounds. For example, the addition of water (eg, 5%) is known to those of ordinary skill in the pharmaceutical industry as a method of simulation for long-term storage to confirm characteristics such as shelf life or stability of the pharmaceutical composition over time. Widely accepted. For example, Jens T. Carstensen (1995) Drug Stability: Principles & Practice, 2d. Ed. , Marcel Dekker, NY, NY, 379-80. In practice, water and heat accelerate the decomposition of some compounds. That is, the effect of water on the pharmaceutical composition is a very important issue because it frequently occurs that moisture and / or moisture is encountered during the manufacture, operation, packaging, storage, shipment and administration of the pharmaceutical composition. .

  The dry pharmaceutical compositions and dosage forms of the present invention can be prepared using active ingredients that are dry or low in water content, and also in low humidity and low humidity conditions. A medicament comprising at least one active ingredient comprising lactose and a primary or secondary amine if it is expected to come into significant contact with moisture and / or high humidity during manufacture, packaging and / or storage The composition and dosage form are preferably dry.

  Dry pharmaceutical compositions need to be prepared and stored so that they remain dry. Accordingly, the dry pharmaceutical composition is preferably packaged using materials known to kit the pharmaceutical composition to prevent exposure to water. Examples of suitable packaging include, but are not limited to, sealed foils, plastics, per dose unit enclosures (eg, vials), blister packs, and strip packs.

  The invention further includes pharmaceutical compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose. Such compounds, referred to herein as “stabilizers,” include, but are not limited to, ascorbic acid, pH buffer, or salt buffer.

  The amount and type of additive, the amount of active ingredient in the dosage form and the individual type may vary depending on factors such as, but not limited to, the route of administration to the patient. However, representative dosage forms of the invention include from about 1 mg to about 1000 mg, preferably from about 50 mg to about 1000 mg of the disclosed compound, or a pharmaceutically acceptable salt, solvate or inclusion compound thereof. 500 mg, most preferably from about 75 mg to about 350 mg. Typically, the disclosed compound, or a pharmaceutically acceptable salt, solvate or inclusion compound thereof, of about 1 mg to 5000 mg per day, preferably about 50 mg to 1500 mg per day, more preferably Is preferably administered in the range of about 75 mg to about 1000 mg. It is easy for a person skilled in the art to determine the appropriate dose and dosage form for an individual patient.

(Oral dosage form)
The pharmaceutical composition of the present invention can be provided as individual dosage forms such as, but not limited to, tablets (eg, chewable tablets), caplets, capsules, and liquids (flavored syrup). Such dosage forms contain a predetermined amount of active ingredient, and can be prepared by methods of pharmacy known to those skilled in the art. See generally Remington's Pharmaceutical Sciences (1990) 18th edition, Mack Publishing, Easton, Pennsylvania.

  A typical oral dosage form of the present invention is prepared by mixing the active ingredients in a mixture containing at least one additive according to conventional pharmaceutical formulation methods. The additive can take various forms depending on the intended method of administration. For example, additives suitable for administration in oral liquid dosage forms or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Also, solid oral dosage forms (eg, powders, tablets, capsules, and caplets) include, but are not limited to, starch, sugar, microcrystalline cellulose, diluent, granulating agent, lubricant, binding Agents, and disintegrants.

  Tablets and capsules are examples of optimal oral dosage units to be used when using solid additives because of their ease of administration. Desirably, the tablets are coated by standard water-soluble or water-insoluble methods. Such dosage forms can be prepared by any pharmaceutical method. In general, pharmaceutical compositions and dosage forms are prepared by uniformly mixing the active ingredient with a liquid base, a finely divided solid base, or both, and then, if necessary, shaping the pharmaceutical into a suitable form. To prepare.

  For example, a tablet can be prepared by compression or molding. In the case of compression, tablets can be prepared by compressing the active ingredient in a dosage form that maintains fluidity, such as powders or granules, optionally mixed with additives, in a suitable machine. In the case of molding, a tablet can be prepared by molding a powder mixture moistened with an inert liquid excipient using an appropriate device.

  Examples of additives that can be used in the oral dosage form of the present invention include, but are not limited to, binders, excipients, disintegrants, and lubricants. Suitable binders for use in pharmaceutical compositions and dosage forms include corn starch, potato starch or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth , Guar gum, cellulose and its derivatives (for example, ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methyl cellulose (for example, Nos. 2208, 2906, 2910), microcrystalline Cellulose and mixtures thereof are included, but are not limited to these.

  Desirable forms of microcrystalline cellulose include AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (FMC Corporation, American Viscose Division, Avisel Sales, Marcus Hook, Pennsylvania) and mixtures thereof, It is not limited to these. An example of a specific binder is a mixture of microcrystalline cellulose and carboxymethyl cellulose sold as AVICEL RC-581. Additives (or additives) that are dry or low in water content include AVICEL-PH-103J and Starch 1500LM.

  Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include talc, calcium carbonate (granular or powdered), microcrystalline cellulose, powdered cellulose, dextrate, kaolin, These include, but are not limited to, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The binder or filler of the pharmaceutical composition of the present invention comprises in particular about 50 to about 99% by weight of the pharmaceutical composition or dosage form.

  Disintegrants are used in the compositions of the invention when preparing tablets that disintegrate when exposed to an aqueous environment. Tablets containing an excessive amount of disintegrant may disintegrate during storage, while tablets containing an excessive amount may not disintegrate at an appropriate rate or under appropriate conditions. Therefore, in order to prepare the solid oral dosage form of the present invention, it is necessary to use a sufficient amount of disintegrant so that it is not too much or too little to affect the release of the active ingredient. There is. The amount of disintegrant used varies with the type of dosage form and can be easily distinguished by one skilled in the art. Exemplary pharmaceutical compositions include about 0.5 to about 15 weight percent disintegrant, preferably about 1 to 5 weight percent disintegrant.

  Disintegrants that can be used in the pharmaceutical compositions and dosage forms of the present invention include agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca Starch, other starches, non-gelatinized starches, other starches, clays, other algins, other celluloses, gums and mixtures thereof include, but are not limited to.

  Lubricants that can be used in the pharmaceutical compositions and dosage forms of the present invention include calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate , Talc, hydrogenated vegetable oils (eg, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, and mixtures thereof However, it is not limited to these. Other lubricants include, for example, Syloid® silica gel (AEROSIL 200, manufacturer: WR Grace, Baltimore, Maryland), and a solidified aerosol of synthetic silica (distributor: Degussa, Plano, Texas). ), CAB-O-SIL (pyrogenic silicon dioxide, distributor: Cabot, Boston, Mass.) And mixtures thereof. When using them, it is desirable to use the lubricant in an amount up to about 1 weight percent of the pharmaceutical composition or dosage form it contains.

(Slow release dosage form)
The active ingredient of the present invention can be administered using sustained release means or transport means well known to those skilled in the art. Examples include the following U.S. Pat. Nos. 3,845,770, 3,916,899, 3,536,809, 3,598,123, and 4,008,719, 5,674,533, 5, 059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556 and 5,733,566 are included. It is not limited to. These are included in the references in this application. Such dosage forms can be used to obtain appropriate release profiles in various ratios, for example, hydropropyl methylcellulose, other polymer matrices, gels, osmotic membranes, osmotic systems, multilayer coatings, microparticles, liposomes, centrosomes. Can be used or used in combination to make one or more active ingredients sustained release. Suitable sustained release dosage forms known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients of the present invention. Accordingly, the present invention includes, but is not limited to, dosage units for oral administration such as tablets, capsules, gel caps, and caplets that are excellent in sustained release.

  All sustained release pharmaceutical compositions have a common goal of enhancing the efficacy of drug therapy over that of non-sustained release pharmaceutical compositions of the same potency. Theoretically speaking, the administration of an optimally designed sustained release pharmaceutical composition in medical treatment is characterized by the use of minimal drugs to treat or control the disease within a minimum amount of time. . Advantages of sustained release pharmaceutical compositions include sustained activity of the drug, reduced frequency of administration, and improved patient compliance. In addition, sustained-release pharmaceutical compositions can be used to affect other characteristics such as the onset of action or the blood concentration of the drug and thereby the incidence of side effects (adverse effects). Can also be affected.

  Most sustained-release pharmaceutical compositions initially release a certain amount of drug (active ingredient) that produces an appropriate therapeutic effect, and then other amounts to maintain this level of therapeutic or prophylactic effect over an extended period of time. Designed to gradually and continuously release drugs. In order to maintain a constant drug concentration in the body, the drug needs to be released from the dosage form at a rate sufficient to compensate for the amount metabolized and excreted from the body. The sustained release of the active ingredient may be stimulated by a variety of conditions including, but not limited to, pH, temperature, enzyme, water or other physiological conditions or compounds.

  Desirable sustained release pharmaceutical compositions in the present invention are further disclosed in spheroids comprising microcrystalline cellulose and optionally hydroxypropylmethyl-cellulose coated with a mixture of ethylcellulose and hydroxypropylmethylcellulose. Or a pharmaceutically acceptable salt, solvate or inclusion compound thereof. Such sustained sustained release pharmaceutical compositions can be prepared according to US Pat. No. 6,274,171, the entire contents of which are incorporated herein.

  Individual sustained release pharmaceutical compositions of the present invention include from about 6% to about 40% by weight of the disclosed compound, from about 50% to about 94% by weight of microcrystalline cellulose (US Pharmaceutical Standard (NF)). ), And optionally, about 0.25% to about 1% by weight of hydroxypropyl-methylcellulose (US Pharmacopeia (USP)), wherein the spheroid is coated with a film coating composition comprising ethylcellulose and hydroxypropylmethylcellulose. including.

(Parenteral dosage form)
Parenteral dosage forms can be administered to a patient by a variety of routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because these methods of administration circumvent a patient's natural defense function, particularly against contamination, parenteral dosage forms are preferably sterilized or rendered sterilizable prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, injectable solutions, dry products that can be dissolved or suspended in pharmaceutically acceptable injectable excipients, injectable suspensions, and emulsions. Is included.

  Suitable excipients that can be used to provide parenteral dosage forms of the invention are well known to those skilled in the art. Examples include, but are not limited to: distilled water USP for injection; water-soluble excipients such as, but not limited to, sodium chloride, Ringer's solution, dextrose, dextrose and sodium chloride, and lactated Ringer's. Water miscible excipients such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl milliliter State and water-insoluble excipients such as benzylbenzoic acid are included.

  Compounds for increasing the solubility of one or more active ingredients disclosed herein can also be included in the parenteral dosage forms of the invention.

(Percutaneous, topical and transmucosal dosage forms)
The transdermal, topical, and transmucosal dosage forms of the present invention include, but are not limited to, ophthalmic solutions, sprays, aerosols, lotions, ointments, gels, solutions, emulsions, suspensions or those skilled in the art. Other known dosage forms are included. For example, Remington's Pharmaceutical Sciences (1980 & 1990) 16th and 18th editions, Mack Publishing, Easton PA and Introduced to Pharmaceutical Dosage Forms (1985) 4th edition, see Lea & Feb. A dosage form suitable for treatment of mucosal tissue in the oral cavity can be formulated as a mouthwash or an oral gel. In addition, transdermal dosage forms include “reservoir type” or “matrix type” patches that can be applied to the skin and allowed to adhere to the skin for a period of time required to penetrate the appropriate amount of active ingredient. Is included.

  Optimal additives (eg, bases and excipients) and other materials that can be used to prepare transdermal, topical, and transmucosal dosage forms included in the present invention are those of the pharmaceutical composition. It is known to those skilled in the art and depends on the particular tissue in which a given pharmaceutical composition or dosage form will be formulated. In view of this, desirable additives for creating a non-toxic and pharmaceutically acceptable lotion, tincture, cream, emulsion, gel or ointment form include, but are not limited to, water, acetone, ethanol, Examples include ethylene glycol, propylene glycol, butane, 1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof. If necessary, moisturizers or humectants can also be added to the pharmaceutical compositions and dosage forms. Such ingredients are known to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences (1980 & 1990) 16th and 18th editions, Mack Publishing, Easton PA.

  Depending on the particular tissue being treated, other pharmaceutical compositions can be used in combination with the active ingredient before or after treatment with the active ingredient of the present invention. For example, penetration enhancers can be used to help transport the active ingredients to the tissue. Permeation enhancers that can be used include: acetone; various alcohols such as ethanol, oleyl alcohol, and tetrahydrofuryl alcohol; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethylformamide; polyethylene glycol; Pyrrolidones such as: Kollidon® grade (Povidone, Polyvidone); Urea; and various water soluble or insoluble sugar esters such as Tween 80 (Polysorbate 80) and Span 60 (Sorbitan monostearate) It is not limited to these.

  The pH of the pharmaceutical composition or dosage form, or the pH of the tissue in which the pharmaceutical composition or dosage form is formulated, may be adjusted to improve the transport of one or more active ingredients. Similarly, transport may be improved by adjusting the polarity, ionic strength, or osmotic pressure of the solvent carrier. Compounds such as stearates can be added to pharmaceutical compositions or dosage forms to change the hydrophilicity or lipophilicity of one or more active ingredients to favorable conditions and improve transport. In this respect, stearates can function as lipid excipients to pharmaceutical compositions, as emulsifiers or surfactants, or as transport enhancers or penetration enhancers. Other salts, hydrates or solvates containing the active ingredient can be used to further adjust the properties of the resulting composition.

(Combination therapy)
In a method for immunosuppression of a patient, or a method for treating or preventing inflammatory diseases and immune diseases, an effective amount of one or more other active ingredients may be administered to a patient who has further been administered a compound of the present invention. included. Such active ingredients can include those conventionally used for immunosuppression or inflammatory diseases or immune diseases. When they are administered in combination with the compounds of the present invention, those other active ingredients are believed to exhibit other effectiveness. For example, other therapeutic agents include, but are not limited to, steroids, non-steroidal anti-inflammatory agents, antihistamines, analgesics, immunosuppressive agents, and compatible mixtures thereof. In such combination therapies, the compounds of the present invention and other agents can also be administered to a subject (eg, human, male or female) together in a conventional manner. The agent may be administered in a single dosage form or in separate dosage forms. Effective amounts of the other therapeutic agents and dosage forms are known to those skilled in the art. Also, determining the range of optimal effective amounts of other therapeutic agents is within the range that would normally be possible for one skilled in the art.

  In one embodiment of the invention, when other therapeutic agents are administered to a subject, the effective amount of the agent of the invention is less than or equal to the effective amount when no other therapeutic agent is administered. In another embodiment, the effective amount of the conventional agent is less than or equal to the effective amount of the conventional agent when the compound of the invention is not administered. By this method, side effects due to the use of a large amount of either drug can be minimized. Other possible utilities (such as, but not limited to, improved drug therapy and / or reduced drug costs) will be apparent to those skilled in the art.

  In one embodiment related to autoimmune and inflammatory diseases, steroids or non-steroidal anti-inflammatory agents can be used as other therapeutic agents. Particularly useful non-steroidal anti-inflammatory agents include aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, pyroprofen, carprofen, oxaprozin, plamoprofen Fen, muroprofen, trioxaprofen, suprofen, aminoprofen, thiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetine, zomepirac, thiopinac, zidometacin, acemetacin, fenthiazac, clidanac, oxypinac, mefenamic acid, meclofenamic acid Flufenamic acid, niflumic acid, tolfenamic acid, diflunisal, flufenisal, piroxicam, sudoxicam, iso Aspirin, sodium salicylate, magnesium choline trisalicylate, salsalate, diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazine; salicylic acid derivatives; paraaminophenol derivatives including acetaminophen and phenacetin; indoles including indomethacin, sulindac, and etodolac And indene acetic acids; heteroaryl acetic acids including tolmethine, diclofenac and ketorolac; anthranilic acids (phenamic acids) including mefenamic acid and meclofenamic acid; enolic acids including oxicam (piroxicam, tenoxicam); and pyrazolidinediones (phenylbutines) , Oxyphentaltazone); and alkanones including nabumetone and pharmaceutically acceptable salts thereof and the like Include mixtures of, but not limited thereto. For a more detailed description of non-steroidal anti-inflammatory drugs (NSAIDs), see Paul A. Insel, Analgesic-Antipyretic and Antiinflammatory Agents and Drugs Employed in the Treatment of Gout, in Goodman & Gilman's The Pharmacological Basis of Therapeutics 617-57 (Perry B.Molinhoff and Raymond W. Ruddon editing, 9th edition 1996) and Glen R . Hanson, Analgesic, Antipyretic and Anti-Inflammatory drugs in Remington: The Science and Practice of Pharmacy II, 1196-1221 (see 19th edition of A. R. Gennaro, 19th edition). All these contents are incorporated herein by reference as constituting the present invention. Of the individual appropriate ones for allergic diseases, other therapeutic agents are considered to be antihistamines. Useful antihistamines include loratadine, cetirizine, fexofenadine, desloratadine, diphenhydrazine, chlorpheniramine, chlorcyclidine, pyriramine, promethazine, terphenazine, doxepin, carbinoxamine, clemastine, tripelenamine, brompheniramine, hydroxyzine, Examples include, but are not limited to, cyclidine, meclizine, cyproheptadine, phenindamine, acribastine, azelastine, levocabastine, and mixtures thereof. For a more detailed description of antihistamines, see Goodman & Gilman's The Pharmaceutical Basis of Therapeutics (2001) 651-57, 10th edition.

  Immunosuppressants include glucocorticoids, corticosteroids (eg prednisone or solmedol), T cell blockers (eg cyclosporin A and FK506), purine analogues (eg azathioprine (Imlan)), pyrimidine analogues (eg: Cytosine arabinoside), alkylating drugs (eg, nitrogen mustard, phenylalanine mustard, busulfan, and cyclophosphamide), folic acid antagonists (eg, aminopterin and methotrexate), antibiotics (eg, rapamycin, actinomycin D) , Mitomycin C, puromycin, and chloramphenicol), human IgG, anti-lymphocyte globulin (ALG), and antibodies (anti-CD3 (OKT3), anti-CD4 (OKT4), anti-CD5, anti-CD7, anti-IL- 2 receptors, anti-al § / beta TCR, anti-ICAM-1, anti-CD20 (Rituxan), antibodies) to anti-IL-12 and immune toxins.

  These and other useful combination therapies will be readily understood and appreciated by those skilled in the art. The potential benefits of such combination therapy include: different efficacy profiles, the ability to minimize toxic side effects by reducing the dose of individual active ingredients, synergies in efficacy, An improvement in the ease of administration or use and / or a reduction in the overall cost of preparing or formulating the compound.

(Other examples)
The compounds of the present invention can also be used as a research tool (eg, as a positive control to evaluate other IL-2 inhibitors). These or other embodiments for the compounds and pharmaceutical compositions of the present invention will be apparent to those skilled in the art.

  The invention is further defined by reference to the following examples describing in detail the preparation of the compounds of the invention. Those skilled in the art will readily be able to make many changes to both materials and methods without departing from the purpose and importance of the present invention. The following examples are intended to aid the understanding of the present invention and should not be construed as limiting the invention to the embodiments described and claimed herein. Substitution of the present invention for any equivalent within the scope of those skilled in the art, now known and later known, as well as changes in pharmaceutical composition or minor changes in experimental design are described herein. Should be considered within the scope of the present invention.

  The contents of all references, including patents and patent applications, cited throughout this specification are hereby incorporated herein by reference in their entirety.

(Materials and general methods)
The reagents and solvents used below are available from vendors such as Aldrich Chemical (Milwaukee, Wisconsin, USA). ¹ H-NMR and ¹³ C-NMR spectra were recorded on a Varian 300MH _Z NMR spectrometer. Significant peaks are summarized in order as follows: δ (ppm): chemical shift, multiplicity (s, singlet; d, doublet; t, triplet; q, quadruple; m, multiplet ; Brs, broad singlet) coupling constant in Hertz (Hz) and proton number.

(General synthesis method)
The preparation methods of the compounds of the present invention are shown in the following reaction formulas 1 to 5. Detailed experimental procedures for individual compounds are described in the (Representative Examples) section below. The compounds of the invention not listed as specific examples can be prepared by appropriate selection of raw materials and routine changes in experimental conditions.

(Representative example)
Example 1 Synthesis of Compounds as Representative Examples of the Present Invention
(Compound 1: 5-difluoromethoxy-1- {4- [2- (2,3-difluoro-phenyl) -2-isocyanovinyl] -phenyl} -3-trifluoromethyl- ¹ H-pyrazole)

  Step 1: Ethanol solution of trifluoroacetoacetic acid ethyl ester (3.68 g, 20 mmol) and 4-hydrohydrazinobenzoic acid (3.77 g, 20 mmol) in ethanol (15 mL) was stirred in a sealed tube for 8 hours at 100 ° C. did. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was triturated with ether / hexane (5: 1 V / V) to give 4- (5-hydroxy-3-trifluoromethyl-pyrazol-1-yl) -benzoic acid ethyl ester (2.67 g, 45% yield). ), A yellowish white solid.

  Step 2: 4- (5-Hydroxy-3-trifluoromethyl-pyrazol-1-yl) benzoic acid ethyl ester (1 g, 3.3 mmol), difluorochloromethane (3 g, 34 mmol) and potassium carbonate (0.5 g, 3.6 mmol) DMF solution (9 mL) was stirred in a sealed tube at −78 ° C. for 3 minutes and then at 100 ° C. for 12 hours. The mixture was cooled at −78 ° C. and the precipitate was removed by filtration and washed with DMF (3 × 1 mL). The filtrate and washings were poured into cold water (200 mL). The resulting suspension was transferred to a centrifuge tube and the contents were centrifuged at room temperature for 10 minutes and further filtered to give 4- (5-difluoromethoxy-3-trifluoromethyl-pyrazol-1-yl). A yellow solid of benzoic acid ethyl ester (1.1 g, 94% yield) was obtained.

Step 3: Stir 4- (5-difluoromethoxy-3-trifluoromethyl-pyrazol-1-yl) -benzoic acid ethyl ester (0.4 g, 1.1 mmol) in anhydrous toluene (8.0 mL) and stir 1M. Of DIBAL-H in toluene (1.33 mL, 1.33 mmol) was added. The resulting solution was stirred for 10 minutes at room temperature. The mixture was quenched with saturated aqueous NH ₄ Cl (40 mL) and extracted with EtOAc (3 × 40 mL). The organic compound was washed with water and brine. The solvent was removed under reduced pressure, chromatography _(SiO 2, 10: 1 hexanes / EtOAc) of the residue obtained by purification, syrup [4- (5-difluoromethoxy-3-trifluoromethyl - pyrazole - 1-Lyl) -phenyl] -methanol (380 mg, 99% yield) was obtained.

Step 4: A solution of 4- (5-difluoromethoxy-3-trifluoromethyl-pyrazo-1-yl) -phenyl] -methanol (380 mg, 1.2 mmol) in DCM (20 mL) was treated with an excess of MnO ₂ , Stir at room temperature for 24 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. Chromatography _(SiO 2, 10: 1 hexanes / EtOAc) purification, syrup 4- (5-difluoromethoxy-3-trifluoromethyl - pyrazole-1-Lil) - benzaldehyde (380 mg, 93% yield) Obtained.

Step 5: 4- (5-Difluoromethoxy-3-trifluoromethyl-pyrazo-1-yl) -benzaldehyde (40.5 mg, 0.13 mmol) and 2,3-difluorobenzylacetonitrile (20.3 mg, 0.13 mmol) ) Was stirred with a 40% aqueous KOH solution (0.1 mL) at room temperature. The mixture was stirred for 1 hour. The resulting white precipitate was collected by filtration, washed with water, and 5-difluoromethoxy-1- {4- [2- (2,3-difluoro-phenyl) -2-isocyano-vinyl] -phenyl} -3-Trifluoromethyl-1H-pyrazole white solid: ¹ H-NMR (CDCl ₃ ) δ 6.39 (s, 1 H), 6.62 (t, 1 H, J = 70.8 Hz), 7.14- 7.28 (m, 2H), 7.36-7.42 (m, 1H), 7.65 (s, 1H), 7.80 (d, 2H, J = 8.7), 8.02 ( d, 2H, J = 8.7) ppm, ESMS is _{C 20 H 10 F 7 N 3} O: 441.1 and calculation; ^{detection: 442.0 (M + H) +} , was obtained.

  The same synthesis was performed in the following examples.

(Compound 2: 3- [4- (5-Difluoromethoxy-3-trifluoromethyl-pyrazo-1-yl) -phenyl] -2- (2-fluoro-phenyl) -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 6.32 (s, 1H), 6.54 (t, 1H, J = 70.8 Hz), 7.14-7.28 (m, 2H), 7.30-7 .40 (m, 1H), 7.55-7.60 (m, 2H), 7.70 (d, 2H, J = 8.7), 7.95 (d, 2H, J = 8.7) ppm. ESMS is _{C 20 H 11 F 6 N 3} O: calculated as 423.1; ^{detection: 424.0 (M + H) +} .

(Compound 3: 3- [4- (5-Difluoromethoxy-3-trifluoromethyl-pyrazo-1-yl) -phenyl] -2- (2,5-difluoro-phenyl) -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 6.39 (s, 1H), 6.62 (t, 1H, J = 70.8 Hz), 7.04-7.21 (m, 2H), 7.30-7 .37 (m, 1H), 7.65 (s, 1H), 7.80 (d, 2H, J = 8.7), 8.02 (d, 2H, J = 8.7) ppm. ESMS is _{C 20 H 10 F 7 N 3} O: calculated as 441.1; ^{detection: 442.0 (M + H) +} .

(Compound 4: 3- [4- (3,5-bis-trifluoromethyl-pyrazol-1-yl) -phenyl] -2- (2,3-difluoro-phenyl) -acrylonitrile)

Step 1: 1,1,1,5,5,5-hexafluoro-pentane-2,4-dione (3.16 g, 15.2 mmol) and 4-hydrazinobenzoic acid hydrochloride (2.86 g, 15.2 mmol) Of ethanol solution (5 mL) was stirred at 100 ° C. for 4 hours in a sealed test tube. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was purified by chromatography _(SiO 2, 4: 1 to 3: 1 hexanes / EtOAc) to give a syrup-like 4- (3,5-bis - trifluoromethyl - pyrazole-1-Lil) - benzoic acid ethyl ester (3.1 g, yield 58%): ¹ H-NMR (CDCl ₃ ) δ 1.40 (t, 3H, J = 7), 4.35-4.50 (m, 2H), 7.10 (s , 1H), 7.60 (d, 2H, J = 7), 8.21 (d, 2H, J = 7) ppm. .

Step 2: A stirred dry toluene solution (20 mL) of 4- (3,5-bis-trifluoromethyl-pyrazol-1-yl) -benzoic acid ethyl ester was added to a 1 M DIBAL-H in toluene solution (10 mL) at room temperature. 2 mL, 10.2 mmol). The mixture was quenched with saturated aqueous NH ₄ Cl (30 mL). The organic compound layers were separated and the aqueous layer was extracted with EtOAc (2 × 30 mL). The organic compound was washed with water, dried over anhydrous Na ₂ SO ₄ aqueous solution (30 mL), and the solvent was removed under reduced pressure. Chromatography _(SiO 2, 4: 1 hexanes / EtOAc) purification, as a colorless oil [4- (3,5-bis - trifluoromethyl - pyrazole-1-Lil) - phenyl] - methanol (2g, yield 94.8%).

Step 3: [4- (3,5-Bis-trifluoromethyl-pyrazol-1-yl) -phenyl] -methanol (2 g) and MnO ₂ (excess) in DCM (30 mL) were stirred at room temperature for 24 hours. . Solid material was removed by filtration and the filtrate was concentrated under reduced pressure. The resultant residue was purified by flash chromatography _(SiO 2, 4: 1 hexanes / EtOAc) to afford the colorless syrup [4- (3,5-bis - trifluoromethyl - pyrazole-1-Lil) - benzaldehyde (1.5 g, yield 76%) was obtained.

Step 4: Stir [4- (3,5-bis-trifluoromethyl-pyrazol-1-yl) -benzaldehyde (0.31 mL, 1 mmol) and 2,3-difluorobenzylacetonitrile (0.15 g, 1 mmol). The ethanol solution (0.85 mL) was treated with 40% KOH (0.23 mL) ethanol solution (0.46 mL) and stirred for 1 hour. The precipitate was collected by filtration, washed with water and 3- [4- (3,5-bis-trifluoromethyl-pyrazol-1-yl) -phenyl] -2- (2,3- Difluoro-phenyl) -acrylonitrile (0.24 g, 52% yield): ¹ H-NMR (CDCl ₃ ) δ 7.13 (s, 1H), 7.18-7.25 (m, 2H), 7.38 -7.44 (m, 1H), 7.66 (d, 2H, J = 8.7), 7.68 (s, 1H), 8.05 (d, 2H, J = 8.7) ppm. ESMS is _{C 20 H 9 F 8 N 3} : 443.0 and calculation; ^{detection: 444.0 (M + H) +} , was obtained.

  The same synthesis was performed in the following examples.

(Compound 5: 3- [4- (3,5-bis-trifluoromethyl-pyrazol-1-yl) -phenyl] -2- (2,5-difluoro-phenyl) -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 7.03-7.22 (m, 3H), 7.26-7.39 (m, 1H), 7.65 (d, 2H, J = 8.7), 7 .68 (s, 1H), 8.05 (d, 2H, J = 8.7) ppm. ESMS is _{C 20 H 9 F 8 N 3} : and the calculated 443.0; ^{detection: 444.0 (M + H) +} .

(Compound 6: 3- [4- (3,5-bis-trifluoromethyl-pyrazol-1-yl) -phenyl] -2- (2-fluoro-phenyl) -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 7.12 (s, 1H), 7.16-7.31 (m, 2H), 7.37-7.46 (m, 1H), 7.60-7.68 (M, 4H), 8.04 (d, 2H, J = 8.7) ppm. ESMS is _{C 20 H 10 F 7 N 3} : and the calculated 425.1; ^{detection: 426.0 (M + H) +} .

(Compound 7: 3- [4- (3,5-bis-trifluoromethyl-pyrazol-1-yl) -phenyl] -2- (2,3-difluoro-phenyl) -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 7.13 (s, 1H), 7.2 (m, 3H), 7.4 (m, 1H), 7.7 (d, 2H, J = 8), 8. 0 (d, 2H, J = 8) ppm. ESMS is _{C 20 H 9 F 8 N 3} : and the calculated 443.1; ^{detection: 444.0 (M + H) +} .

(Compound 8: 3- [4- (3,5-bis-trifluoromethyl-pyrazo-1-yl) -phenyl] -2- (2,3,4-trifluoro-phenyl) -acrylonitrile)
¹ H-NMR (DMSO-d ₆ ) δ 7.6 (m, 2H), 7.8 (d, 2H, J = 9), 7.92 (s, 1H), 8.02 (s, 1H), 8.1 (d, 2H, J = 9) ppm. ESMS is _{C 20 H 8 F 9 N 3} : and the calculated 461.1; ^{detection: 462.0 (M + H) +} .

(Compound 9: 3- [4- (3,5-bis-trifluoromethyl-pyrazo-1-yl) -phenyl] -2- (2,3,6-trifluoro-phenyl) -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 7.0 (m, 1H), 7.14 (s, 1H) 7.3 (m, 1H), 7.42 (s, 1H), 7.7 (d, 2H) , J = 9), 8.1 (d, 2H, J = 9) ppm. ESMS is _{C 20 H 8 F 9 N 3} : 461.1 calculated; ^{detection: 462.0 (M + H) +} .

(Compound 10: 3- [4- (3,5-bis-trifluoromethyl-pyrazo-1-yl) -phenyl] -2- (3,4,5-trifluoro-phenyl) -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 7.14 (s, 1H), 7.4 (m, 2H), 7.53 (s, 1H), 7.7 (d, 2H, J = 9), 8. 1 (d, 2H, J = 9) ppm. ESMS calculated as C ₂₀ H ₈ F ₉ N ₃ : 461.1; detection: 462.1 (M + H) ⁺ .

(Compound 11: 3- [4- (3,5-bis-trifluoromethyl-pyrazo-1-yl) -phenyl] -2- (2,3,5-trifluoro-phenyl) -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 7.0 (m, 1H), 7.13 (s, 1H), 7.2 (m, 1H), 7.7 (d, 2H, J = 9), 7. 70 (s, 1H), 8.1 (d, 2H, J = 9) ppm, ESMS is _{C 20 H 8 F 9 N 3} : and the calculated 461.1; ^{detection: 462.0 (M + H) +} .

(Compound 12: 3- [4- (3,5-bis-trifluoromethyl-pyrazol-1-yl) -phenyl] -2- (3,4,6-trifluoro-phenyl) -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 7.1 (m, 1H), 7.13 (s, 1H), 7.5 (m, 1H), 7.62 (s, 1H), 7.7 (d, 2H, J = 9), 8.0 (d, 2H, J = 9) ppm. ESMS is _{C 20 H 8 F 9 N 3} : and the calculated 461.1; ^{detection: 462.0 (M + H) +} .

(Compound 13: 3- [4- (3,5-bis-trifluoromethyl-pyrazol-1-yl) -2-chloro-phenyl] -2- (2,3-difluoro-phenyl) -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 7.14 (s, 1H), 7.2 (m, 2H), 7.4 (m, 1H), 7.6 (m, 1H), 7.7 (d, 1H, J = 3), 7.9 (s, 1H), 8.3 (d, 1H, J = 9) ppm. ESMS is _{C 20 H 8 ClF 8 N 3} : and the calculated 477.0; ^{detection: 478.3 (M + H) +} .

(Compound 14: 3- [2- (3,5-bis-trifluoromethyl-pyrazol-1-yl) -phenyl] -2- (2,3-difluoro-phenyl) -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 7.0-7.3 (m, 4H), 7.5-7.8 (m, 4H), 8.34 (d, 1H, J = 8) ppm. ESMS is _{C 20 H 89 F 8 N 3} : and the calculated 443.0; ^{detection: 444.0 (M + H) +} .

(Compound 15: 2- (2,5-difluoro-phenyl) -3- [4- (3-methyl-5-trifluoromethyl-pyrazol-1-yl) -phenyl] -acrylonitrile)

To 4-fluorobenzaldehyde (0.43 mL, 4.03 mmol) and 3-methyl-5-trifluoro-pyrazole (727 mg, 4.84 mmol) in DMF solution (5 mL) was added potassium carbonate (0.67 g, 4.84 mmol). The mixture was heated at 120 ° C. for 14 hours. The mixture was diluted with water (50 mL) and extracted with EtOAc. The organic compound layer was washed with water and brine, dried (anhydrous MgSO ₄ ), dried and purified by chromatography (SiO ₂ , 4: 1 hexane / EtOAc) to give 4- (3 -Methyl-5-trifluoromethyl-pyrazol-1-yl) -benzaldehyde (0.87 g, 85% yield) was obtained. ¹ H-NMR (CDCl ₃ ) δ 2.44 (s, 3H), 6.51 (s, 1H), 7.7 (d, 2H, J = 9), 8.1 (d, 2H, J = 9) ) 10.10 (s, 1 H) ppm. ESMS is _{C 12 H 9 F 3 N 2} O: was calculated as 254.1; ^{detection: 255.0 (M + H) +} .

4- (3-Methyl-5-trifluoromethyl-pyrazol-1-yl) -benzaldehyde (127 mg, 0.50 mmol) and 2,5-difluoro-phenylacetonitrile (77 mg, 0.50 mmol) in ethanol (4 mL) were added. To the stirred mixture was added 0.5 mL of water soluble 6N KOH at room temperature. The mixture was stirred for 2 hours, and the resulting precipitate was collected by filtration and treated as a white solid with 2- (2,5-difluoro-phenyl) -3- [4- (3-methyl-5-trimethyl). Fluoromethyl-pyrazol-1-yl) -phenyl] -acrylonitrile (170 mg, 87% yield) was obtained: ¹ H-NMR (CDCl ₃ ) δ 2.45 (s, 3H), 6.51 (s, 1H), 7.1 (m, 2H), 7.3 (m, 1H), 7.6 (d, 2H, J = 9), 7.67 (s, 1H), 8.0 (d, 2H, J = 9) ppm. ESMS is _{C 20 H 12 F 5 N 3} : 389.1; and calculated; ^{detection: 390.0 (M + H) +} .

(Compound 16: 2- (2,4-difluoro-phenyl) -3- [4- (3-trifluoromethyl-pyrazol-1-yl) -phenyl] -acrylonitrile)
¹ H-NMR (DMSO-d ₆ ) δ 7.12 (d, 1H, J = 2), 7.3 (m, 1H), 7.5 (m, 1H), 7.8 (m, 1H), 7.87 (s, 1H), 8.0 (m, 4H), 8.87 (d, 1H, J = 2) ppm. ESMS was calculated as C ₁₉ H ₁₀ F ₅ N ₃ : 375.1; detection: 376.0 (M + H) ⁺ .

(Compound 17: 2- (2,3-difluoro-phenyl) -3- [4- (3-trifluoromethyl-pyrazol-1-yl) -phenyl] -acrylonitrile)
¹ H-NMR (DMSO-d ₆ ) δ 7.12 (d, 1H, J = 3), 7.4 (m, 1H), 7.5 (m, 1H), 7.97 (s, 1H), 8.1 (m, 5H), 8.87 (d, 1H, J = 3) ppm. ESMS was calculated as C ₁₉ H ₁₀ F ₅ N ₃ : 375.1; detection: 376.0 (M + H) ⁺ .

(Compound 18: 2- (2,3-difluoro-phenyl) -3- [4- (3-methyl-5-trifluoromethyl-pyrazol-1-yl) -phenyl] -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 2.45 (s, 3H), 6.51 (s, 1H), 7.2 (m, 2H), 7.4 (m, 1H), 7.6 (d, 2H, J = 8), 7.67 (s, 1H), 8.0 (d, 2H, J = 8) ppm. ESMS is _{C 20 H 12 F 5 N 3} : 389.1; and calculated; ^{detection: 390.0 (M + H) +} .

(Compound 19: 2- (2,4-difluoro-phenyl) -3- [4- (3-methyl-5-trifluoromethyl-pyrazol-1-yl) -phenyl] -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 2.44 (s, 3H), 6.51 (s, 1H), 6.9 (m, 2H), 7.6 (m, 4H), 8.0 (d, 2H, J = 9) ppm. ESMS is _{C 20 H 12 F 5 N 3} : 389.1; and calculated; ^{detection: 390.0 (M + H) +} .

(Compound 20: 2- (2,6-difluoro-phenyl) -3- [4- (3-methyl-5-trifluoromethyl-pyrazol-1-yl) -phenyl] -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 2.44 (s, 3H), 6.51 (s, 1H), 7.0 (t, 2H, J = 8), 7.4 (m, 2H), 7. 6 (d, 2H, J = 9), 8.0 (d, 2H, J = 9) ppm. ESMS is _{C 20 H 12 F 5 N 3} : 389.1; and calculated; ^{detection: 390.1 (M + H) +} .

(Compound 21: 2- (3,4-difluoro-phenyl) -3- [4- (3-methyl-5-trifluoromethyl-pyrazol-1-yl) -phenyl] -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 2.45 (s, 3H), 6.51 (s, 1H), 7.3 (m, 1H), 7.5 (m, 3H), 7.6 (d, 2H, J = 8), 8.0 (d, 2H, J = 8) ppm. ESMS is _{C 20 H 12 F 5 N 3} : 389.1; and calculated; ^{detection: 390.0 (M + H) +} .

(Compound 22: 2- (3,5-difluoro-phenyl) -3- [4- (3-methyl-5-trifluoromethyl-pyrazol-1-yl) -phenyl] -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 2.45 (s, 3H), 6.52 (s, 1H), 6.9 (m, 1H), 7.3 (m, 2H), 7.60 (s, 1H), 7.6 (d, 2H, J = 8), 8.0 (d, 2H, J = 8) ppm. ESMS is _{C 20 H 12 F 5 N 3} : 389.1; and calculated; ^{detection: 390.1 (M + H) +} .

(Compound 23: 2-phenyl-3- (4-pyrazo-1-yl-phenyl) -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 6.51-6.54 (m, 1H), 7.40-7.51 (m, 3H), 7.54 (s, 1H), 7.66-7.73 (M, 2H), 7.77 (d, 1H, J = 1.2), 7.80-7.86 (m, 2H), 7.98-8.05 (m, 3H) ppm. ESMS is _{C 18 H 13 N 3: 271.1} ; and calculated; ^{detection: 272.0 (M + H) +} .

(Compound 24: 2- (2,5-difluoro-phenyl) -3- (4-pyrazo-1-yl-phenyl) -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 6.51-6.54 (m, 1H), 7.04-7.22 (m, 2H), 7.28-7.38 (m, 1H), 7.62 (S, 1H), 7.77 (s, 1H), 7.85 (d, 2H, J = 8), 8.00 (s, 1H), 8.04 (d, 2H, J = 8) ppm . ESMS is _{C 18 H 11 F 2 N 3} : 307.1; and calculated; ^{detection: 308.0 (M + H) +} .

(Compound 25: 3- [4- (3,5-bis-trifluoromethyl-pyrazo-1-yl) -phenyl] -2- (2,3-difluoro-benzoyl) -acrylonitrile)

To a stirred 2,3-difluoroacetophenone (5.40 g, 34.6 mmol) EtOAc solution (100 mL) was treated dropwise with bromine (1.77 mL, 34.6 mmol) at room temperature and the mixture was stirred for 30 minutes. The solvent was removed under reduced pressure to give the intermediate bromide as a yellow oil. The oil was cooled to 0 ° C., treated with NaCN (2.94 g, 60 mmol) and stirred for 2 hours. The mixture was acidified with 5% aqueous citric acid (100 mL) and extracted with EtOAc. The organic compound layer was dried (anhydrous MgSO ₄ ), evaporated to moisture and purified by chromatography (SiO ₂ , 4: 1 hexane / EtOAc) to give 3- (2,3-difluoro-phenyl) as a yellow solid. -3-Oxo-propionitrile (1.19 g, 19% yield): ¹ H-NMR (CDCl ₃ ) δ 4.08 (s, 2H), 7.2 (m, 1H), 7.5 (m , 1H), 7.7 (m, 1H) ppm. ESMS was calculated as C ₉ H ₅ F ₂ NO: 181.0; detection: 182.0 (M + H) ⁺ .

4- (3,5-bis-trifluoromethyl-pyrazo-1-yl) -benzaldehyde (0.18 g, 0.58 mmol), 3- (2,3-difluoro-phenyl) -3-oxo-propionitrile An anhydrous benzene solution of (0.1 g, 0.55 mmol) and piperidine acetate (8 mg, 0.06 mmol) was heated at reflux for 12 hours. Volatile components were removed under reduced pressure to give a syrup. Trituration with ether and 3- [4- (3,5-bis-trifluoromethyl-pyrazol-1-yl) -phenyl] -2- (2,3-difluoro-benzoyl) -acrylonitrile as a solid (0.18 g, yield 65%): ¹ H-NMR (CDCl ₃ ) δ 7.15 (s, 1H), 7.24-7.32 (m, 1H), 7.38-7.50 (m , 2H), 7.72 (d, 2H, J = 8.4), 8.11 (s, 1H), 8.20 (d, 2H, J = 8.4) ppm. ESMS is _{C 21 H 9 F 8 N 3} O: 471.1 and calculated; ^{detection: 472.0 (M + H) +} , was obtained.

  The same synthesis was performed in the following examples.

(Compound 26: 2-benzoyl-3- [4- (5-trifluoromethyl-pyrazo-1-yl) -phenyl] -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 6.80 (d, 1H, J = 2.4), 7.20 (d, 1H, J = 9), 7.50-7.58 (m, 2H), 7 .62-7.73 (m, 1H), 7.89-7.94 (m, 1H), 7.92 (d, 2H, J = 9), 8.03-8.14 (m, 2H) , 8.18 (d, 2H, J = 8.7) ppm. ESMS is _{C 20 H 12 F 3 N 3} O: calculated as 367.1; ^{detection: 368.1 (M + H) +} .

(Compound 27: 2- (furan-2-carbonyl) -3- [4- (5-trifluoromethyl-pyrazol-1-yl) -phenyl] -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 6.65-6.70 (m, 1H), 6.80 (d, 1H, J = 2.1), 7.21 (d, 1H, J = 9), 7 .78 (d, 2H, J = 4.2), 7.92 (d, 2H, J = 8.7), 8.05-8.18 (m, 1H), 8.20 (d, 2H, J = 8.7), 8.37 (bs, 1H) ppm. ESMS is _{C 18 H 10 F 3 N 2} O 2: calculated as 357.1; ^{detection: 358.0 (M + H) +} .

(Compound 28: 2-benzoyl-3- [4- (3-thiophen-2-nyl-pyrazol-1-yl) -phenyl] -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 6.78 (s, 1H), 7.11 (s, 1H), 7.30-7.38 (m, 1H), 7.42-7.70 (m, 4H) ), 7.85-7.98 (m, 4H), 8.06 (d, 2H, J = 9), 8.16 (d, 2H, J = 7) ppm. ESMS is _C 23 _H 15 _N 3 OS: calculated as 381.1; ^{detection: 382.0 (M + H) +} .

(Compound 29: 2- (furan-2-carbonyl) -3- [4- (3-methyl-pyrazol-1-yl) -phenyl] -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 2.40 (s, 3H), 6.33 (d, 1H, J = 2.1), 6.65 (dd, 1H, J = 1.8; 3.0) , 7.76 (m, 1H), 7.78 (d, 1H, J = 3.9), 7.84 (d, 2H, J = 9), 7.94 (d, 1H, J = 2. 4), 8.18 (d, 2H, J = 9), 8.37 (s, 1H) ppm. ESMS is _{C 18 H 13 N 3 O 2} : calculated as 303.1; ^{detection: 304.0 (M + H) +} .

(Compound 30: 2-benzoyl-3- (4-pyrazo-1-yl-phenyl) -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 6.54 (dd, 1H, J = 1.8; 2.0), 7.54 (t, 2H, J = 7.5), 7.65 (t, 1H, J = 7.2), 7.79 (d, 1H, J = 1.2), 7.86-7.94 (m, 4H), 8.04 (d, 2H, J = 2.4), 8.16 (d, 2H, J = 8.7) ppm. ESMS is _C 19 _H 13 _N 3 O: calculated as 299.1; ^{detection: 300.0 (M + H) +} .

(Compound 31: 2- (furan-2-carbonyl) -3- [4- (3-phenyl-pyrazo-1-yl) -phenyl] -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 6.66 (dd, 1H, J = 1.8; 3.8), 6.86 (d, 1H, J = 2.4), 7.38 (t, 2H, J = 7), 7.46 (t, 2H, J = 7), 7.77 (s, 1H), 7.79 (d, 1H, J = 3.6), 7.94 (d, 1H, J = 7), 7.97 (d, 2H, J = 9), 8.08 (d, 1H, J = 2.7), 8.21 (d, 2H, J = 8), 8.39 ( s, 1H) ppm. ESMS is _{C 23 H 15 N 3 O 2} : calculated as 365.1; ^{detection: 366.0 (M + H) +} .

(Compound 32: 3- [4- (3,5-bis-trifluoromethyl-pyrazol-1-yl) -phenyl] -2- (2,3-difluoro-benzoyl) -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 7.15 (s, 1H), 7.24-7.32 (m, 1H), 7.38-7.50 (m, 2H), 7.72 (d, 2H) , J = 8.4), 8.11 (s, 1H), 8.20 (d, 2H, J = 8.4), ppm. ESMS is _{C 21 H 9 F 8 N 3} O: calculated as 471.1; ^{detection: 472.0 (M + H) +} .

(Compound 33: 3- [4- (3,5-bis-trifluoromethyl-pyrazo-1-yl) -phenyl] -2- (furan-2-carbonyl) -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 6.68 (dd, 1H, J = 2.1; 3.6), 7.15 (s, 1H), 7.72 (d, 2H, J = 8.7) , 7.79 (s, 1H), 7.80 (d, 1H, J = 5), 8.21 (d, 2H, J = 8.7), 8.04 (bs, 1H) ppm. ESMS is _{C 19 H 9 F 6 N 3} O 2: calculated as 425.1; ^{detection: 426.0 (M + H) +} .

(Compound 34: 3- [4- (3,5-bis-trifluoromethyl-pyrazol-1-yl) -phenyl] -2- (2,4-difluoro-benzoyl) -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 6.82-7.12 (m, 2H), 7.15 (s, 1H), 7.67-7.76 (m, 3H), 8.10 (s, 1H ), 8.15-8.23 (m, 2H) ppm. ESMS is _{C 21 H 9 F 8 N 3} O: calculated as 471.1; ^{detection: 472.0 (M + H) +} .

(Compound 35: 2- (2,3-difluoro-benzoyl) -3- [4- (3-phenyl-pyrazol-1-yl) -phenyl] -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 6.87 (d, 1H, J = 2.7), 7.22-7.31 (m, 1H), 7.34-7.50 (m, 5H), 7 .91-7.97 (m, 2H), 7.98 (d, 2H, J = 8.7), 8.09 (d, 2H, J = 2.4), 8.20 (d, 2H, J = 8.7) ppm. ESMS is _{C 25 H 15 F 2 N 3} O: calculated as 411.1; ^{detection: 412.1 (M + H) +} .

(Compound 36: 2- (2,3-difluoro-benzoyl) -3- [4- (3-methyl-5-trifluoromethyl-pyrazol-1-yl) -phenyl] -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 2.46 (s, 3H), 6.56 (s, 1H), 7.3 (m, 1H), 7.4 (m, 2H), 7.7 (d, 2H, J = 9), 8.10 (s, 1H), 8.2 (d, 2H, J = 9) ppm. ESMS is _{C 21 H 12 F 5 N 3} O: calculated as 417.1; ^{detection: 418.1 (M + H) +} .

(Compound 37: 2- (2,4-difluoro-benzoyl) -3- [4- (3-trifluoromethyl-pyrazol-1-yl) -phenyl] -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 6.81 (s, 1H), 7.0 (m, 2H), 7.7 (m, 1H), 7.9 (d, 1H, J = 9), 8. 1 (d, 2H, J = 7), 8.2 (d, 2H, J = 9) ppm. ESMS is _{C 20 H 10 F 5 N 3} O: calculated as 403.1; ^{detection: 404.0 (M + H) +} .

(Compound 38: 2- (2,3-difluoro-benzoyl) -3- [4- (3-trifluoromethyl-pyrazol-1-yl) -phenyl] -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 6.80 (s, 1H), 7.2-7.5 (m, 3H), 7.9 (d, 1H, J = 9), 8.1 (d, 2H) , J = 7), 8.2 (d, 2H, J = 9) ppm. ESMS is _{C 20 H 10 F 5 N 3} O: calculated as 403.1; ^{detection: 404.0 (M + H) +} .

(Compound 39: 2- (2,4-difluoro-benzoyl) -3- [4- (3-methyl-5-trifluoromethyl-pyrazol-1-yl) -phenyl] -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 2.48 (s, 3H), 6.56 (s, 1H), 7.0 (m, 2H), 7.77 (m, 3H), 8.10 (s, 1H), 8.2 (d, 2H, J = 9) ppm. ESMS is _{C 21 H 12 F 5 N 3} O: calculated as 417.1; ^{detection: 418.0 (M + H) +} .

(Compound 40: 2- (2,5-difluoro-benzoyl) -3- [4- (3-methyl-5-trifluoromethyl-pyrazol-1-yl) -phenyl] -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 2.44 (s, 3H), 6.58 (s, 1H), 7.2-7.4 (m, 3H), 7.77 (d, 2H, J = 9) ), 8.10 (s, 1H), 8.2 (d, 2H, J = 9) ppm. ESMS is _{C 21 H 12 F 5 N 3} O: calculated as 417.1; ^{detection: 418.0 (M + H) +} .

(Compound 41: 2- (2,5-difluoro-benzoyl) -3- [4- (3-trifluoromethyl-pyrazol-1-yl) -phenyl] -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 6.80 (s, 1H), 7.2-7.4 (m, 3H), 7.9 (d, 2H, J = 9), 8.08 (s, 1H ), 8.2 (d, 2H, J = 9) ppm. ESMS is _{C 20 H 10 F 5 N 3} O: calculated as 403.1; ^{detection: 404.0 (M + H) +} .

(Compound 42: 2- (2,5-difluoro-phenyl) -3- [4- (3-trifluoromethyl-pyrazol-1-yl) -phenyl] -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ6.8 (d, 1H, J = 6), 7.1 (m, 2H), 7.4 (m, 1H), 7.65 (s, 1H), 7. 9 (d, 2H, J = 8), 8.0 (m, 3H) ppm. ESMS is _{C 19 H 10 F 5 N 3} : and the calculated 375.1; ^{detection: 376.0 (M + H) +} .

(Compound 43: 3- [3- (3,5-bis-trifluoromethyl-pyrazol-1-yl) -phenyl] -2- (2,3-difluoro-phenyl) -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 7.13 (s, 1H), 7.2 (m, 2H), 7.4 (m, 1H), 7.7 (m, 3H), 7.9 (m, 1H), 8.2 (m, 1H) ppm. ESMS is _{C 20 H 9 F 8 N 3} : and the calculated 443.1; ^{detection: 444.0 (M + H) +} .

(Compound 44: 3- [3- (3,5-bis-trifluoromethyl-pyrazol-1-yl) -phenyl] -2- (2,5-difluoro-phenyl) -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 7.13 (s, 1H), 7.1 (m, 2H), 7.4 (m, 1H), 7.7 (m, 3H), 8.0 (m, 1H), 8.2 (m, 1H) ppm. ESMS is _{C 20 H 9 F 8 N 3} : and the calculated 443.1; ^{detection: 444.0 (M + H) +} .

(Compound 45: 2- (2,3-difluoro-phenyl) -3- [4- (2-trifluoromethyl-benzimidazo-1-yl) -phenyl] -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 7.2 (m, 3H), 7.4 (m, 3H), 7.6 (m, 2H), 7.72 (s, 1H), 8.0 (m, 1H), 8.1 (m, 2H) ppm. ESMS is _{C 23 H 12 F 5 N 3} : and the calculated 425.1; ^{detection: 426.1 (M + H) +} .

(Compound 46: 2- (2,5-difluoro-phenyl) -3- [4- (2-trifluoromethyl-benzimidazo-1-yl) -phenyl] -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 7.2 (m, 3H), 7.4 (m, 1H), 7.5 (m, 2H), 7.6 (m, 2H), 7.76 (s, 1H), 8.0 (m, 1H), 8.2 (m, 2H) ppm. ESMS is _{C 23 H 12 F 5 N 3} : and the calculated 425.1; ^{detection: 426.1 (M + H) +} .

(Compound 47: 3- [4- (3,5-bis-trifluoromethyl-pyrazol-1-yl) -phenyl] -2- (3,4-difluoro-benzoyl) -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 7.13 (s, 1H), 7.40 (m, 1H), 7.44-7.58 (m, 3H), 7.65 (d, 2H, J = 9) ), 8.2 (d, 2H, J = 9) ppm. ESMS is _{C 21 H 9 F 8 N 3} O: calculated as 471.1; ^{detection: 472.1 (M + H) +} .

(Compound 48: 2- (2-fluoro-phenyl) -3- (4-pyrazo-1-yl-phenyl) -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 6.53-6.55 (m, 1H), 7.39-7.52 (m, 3H), 7.54 (s, 1H), 7.64-7.74 (M, 2H), 7.78 (d, 1H, J = 2), 7.80-7.86 (m, 1H), 7.99-8.10 (m, 3H) ppm. ESMS is _C 18 _H 12 _FN 3: and the calculated 289.1; ^{detection: 290.1 (M + H) +} .

(Compound 49: 2- (2,5-difluoro-cyclohexa-2,4-dienyl) -3- [4- (3-methyl-pyrazo-1-yl) -phenyl] -acrylonitrile)
¹ H-NMR (CDCl ₃ ) δ 2.40 (s, 3H), 6.30 (d, 1H, J = 2), 7.01-7.20 (m, 2H), 7.25-7.35 (M, 1H), 7.60 (s, 1H), 7.81 (d, 2H, J = 9), 7.90 (d, 1H, J = 2), 8.00 (d, 2H, J = 9) ppm. ESMS is _{C 19 H 13 F 2 N 3} : and the calculated 321.1; ^{detection: 322.0 (M + H) +} .

Example 2: Inhibition of IL-2 production in human Jurkat cell line using compounds of the invention
Jurkat cells (ATCC, Cat # TIB-152) were grown in RPMI 1640 medium (Cat # 30-2001) containing 10% FBS. For compound screening, Jurkat cells were spread in 96-well plates at a density of 500,000 cells per well in RPMI 1640 medium containing 1% FBS. Various concentrations of each test compound were then added to the cell plate and PHA (Sigma, Cat # L-9017) was added at a final concentration of 2.5 μg / ml to stimulate IL-2 production. After 20 hours of incubation, the cell plate was centrifuged at 500-800 g for 5 minutes, the supernatant was collected and a human IL-2 enzyme-labeled immunosorbent assay (ELISA) kit (Cat # 851) purchased from Cell Sciences. , 500,020) for IL-2 detection. An ELISA assay for IL-2 production was performed in 96-well plates according to the protocol provided by Cell Sciences.

IC ₅₀ (ie, the concentration at which IL-2 release is inhibited by 50%) was determined and the results are shown in the table. As is apparent from these results, the compounds of the present invention are effective in inhibiting IL-2 release. The symbol “A” in the table means an IC ₅₀ of 0.010 μM or less, the symbol “B” means an IC ₅₀ between 0.010 and 1.0 μM, and the symbol “C” means 1 μM. Means an IC ₅₀ exceeding.

なお、上表中の記号“｛”又は“｝”は、基の結合部位を示す。

In addition, the symbol “{” or “}” in the above table indicates a binding site of the group.

Claims (25)

A compound represented by the following structural formula (I), or a pharmaceutically acceptable salt, solvate or inclusion compound containing the compound:

(Where Cy ¹ is a monocyclic or bicyclic aromatic or non-aromatic carbocyclyl or heterocyclyl compound;
Y is a monocyclic or bicyclic, aromatic or non-aromatic carbocyclyl or heterocyclyl group;
R ¹ is = O, = S, = NOR ⁴ or = C (R ⁵ ) (R ⁵ ),
R ² is a monocyclic or polycyclic, non-aromatic or aromatic carbocyclyl or heterocyclyl group, and when R ¹ is ═O, R ² is one or more halogen, lower perfluoroalkyl or lower perfluoro group. It is a phenyl group substituted with fluoroalkoxy, or R ¹ and R ² can be combined to form a monocyclic or polycyclic, non-aromatic or aromatic carbocyclyl or heterocyclyl group. ,
Each R ³ is a substituent bonded to Cy ¹ and is independently halogen, lower alkyl, lower halogen alkyl, lower alkoxy, lower halogen alkoxy, CN, NO ₂ , OR ⁴ , N (R ⁴ ) (R ⁴ ), SR ⁴ , CO ₂ R ⁴ , CON (R ⁴ ) (R ⁴ ), SOR ⁶ , SO ₂ R ⁶ , COR ⁴ , NR ⁴ COR ⁴ , NR ⁴ CON (R ⁴ ) (R ⁴ ), SO ₂ Selected from N (R ⁴ ) (R ⁴ ), NR ⁴ SOR ⁶ and Ar ² ;
n is an integer selected from 0, 1, 2 or 3;
Each Ar ² is independently halogen, lower alkyl, lower halogen alkyl, lower alkoxy, lower halogen alkoxy, CN, NO ₂ , R ⁶ , OR ⁴ , N (R ⁴ ) (R ⁴ ), SR ⁴ , CO _2. R ⁴ , CON (R ⁴ ) (R ⁴ ), SOR ⁶ , SO ₂ R ⁶ , COR ⁴ , NR ⁴ COR ⁴ , NR ⁴ CON (R ⁴ ) (R ⁴ ), SO ₂ N (R ⁴ ) (R ⁴ ) or an aryl or heteroaryl group optionally substituted with NR ⁴ SOR ⁶ ;
Each R ⁴ is independently hydrogen, or one or more amino, alkylamino, alkoxy, alkylthio, oxo (═O), thio (═S), imino (═NH), alkylimino (═N-alkyl) , Halogen, acyl, nitro, hydroxy, cyano, aryl, alkylaryl, aryloxy, arylthio, arylamino, carbocyclyl, carbocyclyloxy, carbocyclylthio, carbocyclylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino or heterocyclylthio An alkyl group optionally substituted with a group,
Each R ⁵ is independently CN or CO ₂ R ⁴ , and each R ⁶ is independently one or more amino, alkylamino, alkoxy, alkylthio, oxo (═O), thio (═S) , Imino (= NH), alkylimino (= N-alkyl), halogen, acyl, nitro, hydroxy, cyano, aryl, alkylaryl, aryloxy, arylthio, arylamino, carbocyclyl, carbocyclyloxy, carbocyclylthio, An alkyl group optionally substituted with a carbocyclylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino or heterocyclylthio group. ) Phenyl Cy ¹ is fused benzene, pyridine, pyrimidine, triazine, tetrazine, furan, thiophene, pyrrole, oxazole, imidazole, thiazole, isoxazole, optionally with pyrazole or isothiazole, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl The compound of claim 1, which is a thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiazolyl or thiadiazolyl group. Cy ¹ is a group represented by the following structural formula (II), (III), (IV), (V), (VI), (VII), (VIII), (X) (XI) or (XII) The compound of claim 1, wherein

(Wherein the individual structural formulas (I) to (XII) are optionally fused with benzene, pyridine, pyrimidine, triazine, tetrazine, furan, thiophene, pyrrole, oxazole, imidazole, thiazole, isoxazole, pyrazole or isothiazole. ,
Z is O, S or NR ⁴ and each X is independently CH, CR ³ or N. ) The compound according to claim 1, which is represented by the following structural formula.

(Where R ¹ is ═O, ═S, ═NOR ⁴ or ═C (R ⁵ ) ₂ , R ² is an aryl, cycloalkyl, bicycloalkyl, cycloalkenyl, bicycloalkenyl or heterocyclyl group; ^{When 1} is ═O, R ² is a phenyl group substituted with one or more halogen, lower perfluoroalkyl or lower perfluoroalkoxy groups, or R ¹ and R ² are combined to form aryl, cyclo Forming an alkyl, bicycloalkyl, cycloalkenyl, bicycloalkenyl or heterocyclyl group.) R ¹ and aryl R ² are integrated, cycloalkyl, bicycloalkyl, cycloalkenyl, to form a bicycloalkenyl or heterocyclyl group, the compound according to claim 4. The compound according to claim 5, wherein the group formed by integrating R ¹ and R ² is an optionally substituted phenyl group. The compound according to claim 6, wherein the group formed by integrating R ¹ and R ² is a phenyl group substituted by one or more halogen, a lower perfluoroalkoxy or a lower perfluoroalkyl group. 5. A compound according to claim 4, wherein R < ¹ > is C = O. A compound represented by the following structural formula, or a pharmaceutically acceptable salt, solvate or inclusion compound containing the compound.

(Where Cy ¹ is a monocyclic or bicyclic aromatic or non-aromatic carbocyclyl or heterocyclyl group;
Q is CH or N;
Ring A is optionally substituted at any substitutable carbon atom position and is optionally fused with an optionally substituted phenyl ring;
R ¹ is = O, = S, = NOR ⁴ or = C (R ⁵ ) (R ⁵ ),
R ² is a monocyclic or polycyclic, non-aromatic or aromatic carbocyclyl or heterocyclyl group, and when R ¹ is ═O, R ² is one or more halogen, lower perfluoroalkyl or lower It is a phenyl group substituted with a perfluoroalkoxy group, or R ¹ and R ² can be combined to form a monocyclic or polycyclic, non-aromatic or aromatic carbocyclyl or heterocyclyl group so,
Each R ³ is a substituent bonded to Cy ¹ and is independently halogen, lower alkyl, lower halogen alkyl, lower alkoxy, lower halogen alkoxy, CN, NO ₂ , OR ⁴ , N (R ⁴ ) (R ⁴ ), SR ⁴ , CO ₂ R ⁴ , CON (R ⁴ ) (R ⁴ ), SOR ⁶ , SO ₂ R ⁶ , COR ⁴ , NR ⁴ COR ⁴ , NR ⁴ CON (R ⁴ ) (R ⁴ ), SO ₂ Selected from N (R ⁴ ) (R ⁴ ), NR ⁴ SOR ⁶ and Ar ² ;
n is an integer selected from 0, 1, 2 or 3;
Each Ar ² is independently halogen, lower alkyl, lower halogen alkyl, lower alkoxy, lower halogen alkoxy group, CN, NO ₂ , R ⁶ , OR ⁴ , N (R ⁴ ) (R ⁴ ), SR ⁴ , CO ₂ R ⁴ , CON (R ⁴ ) (R ⁴ ), SOR ⁶ , SO ₂ R ⁶ , COR ⁴ , NR ⁴ COR ⁴ , NR ⁴ CON (R ⁴ ) (R ⁴ ), SO ₂ N (R ⁴ ) ( An aryl or heteroaryl group optionally substituted with R ⁴ ) or NR ⁴ SOR ⁶ ;
Each R ⁴ is independently hydrogen, or one or more amino, alkylamino, alkoxy, alkylthio, oxo (═O), thio (═S), imino (═NH), alkylimino (═N-alkyl) , Halogen, acyl, nitro, hydroxy, cyano, aryl, alkylaryl, aryloxy, arylthio, arylamino, carbocyclyl, carbocyclyloxy, carbocyclylthio, carbocyclylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino or heterocyclylthio An alkyl group optionally substituted with a group,
Each R ⁵ is independently CN or CO ₂ R ⁴ , and each R ⁶ is independently one or more amino, alkylamino, alkoxy, alkylthio, oxo (═O), thio (═S) , Imino (= NH), alkylimino (= N-alkyl), halogen, acyl, nitro, hydroxy, cyano, aryl, alkylaryl, aryloxy, arylthio, arylamino, carbocyclyl, carbocyclyloxy, carbocyclylthio, An alkyl group optionally substituted with a carbocyclylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino or heterocyclylthio group. ) Cy ¹ is optionally fused with benzene, pyridine, pyrimidine, triazine, tetrazine, furan, thiophene, pyrrole, oxazole, imidazole, thiazole, isoxazole, pyrazole or isothiazole, phenyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, tetrazolyl 10. A compound according to claim 9, which is a group, furyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiazolyl or thiadiazolyl group. Cy ¹ is represented by the following structural formula (II), (III), (IV), (V), (VI), (VII), (VIII), (X), (XI) or (XII):

A group represented by
The individual structural formulas (I) to (XII) are optionally fused with benzene, pyridine, pyrimidine, triazine, tetrazine, furan, thiophene, pyrrole, oxazole, imidazole, thiazole, isoxazole, pyrazole or isothiazole,
Z is O, S or NR ^4, and the individual X is independently CH, CR ³ or N, A compound according to claim 9.   10. A compound according to claim 9, wherein Q is CH and ring A is optionally substituted at any substitutable carbon atom position. The compound according to claim 12, which is represented by the following structural formula.

The compound according to claim 13, wherein the group formed by combining R ¹ and R ² is an optionally substituted phenyl group. Ring A and the phenyl ring formed by integrating R ¹ and R ² are optionally and independently halogen, lower alkyl, lower halogen alkyl, lower alkoxy, lower halogen alkoxy, CN, NO ₂ , R ⁶ , OR ⁴ , N (R ⁴ ) (R ⁴ ), SR ⁴ , CO ₂ R ⁴ , CON (R ⁴ ) (R ⁴ ), SOR ⁶ , SO ₂ R ⁶ , COR ⁴ , NR ⁴ COR ⁴ , NR ⁴ CON ( _{^{R 4) (R 4),}} SO 2 N (R 4) (R 4) and ^NR 4 substituted by one or more groups independently selected from the SOR ^6, a compound according to claim 14 . The compound of claim 15, which is represented by the structural formula:

(Wherein R ¹⁰ and R ¹¹ are independently hydrogen, lower alkyl, lower halogen alkyl, furanyl, thienyl, phenyl, lower alkoxy or lower halogen alkoxy groups, and R ³ is independently hydrogen, lower alkyl. , Lower halogenalkyl, lower alkoxy or lower halogenalkoxy group.) The phenyl ring formed from R ¹ and R ² is substituted with one or more halogen, lower perfluoroalkyl or lower perfluoroalkoxy groups, and R ¹⁰ and R ¹¹ are independently hydrogen, lower alkyl or lower perfluoro The compound according to claim 16, which is an alkyl group. 14. A compound according to claim 13, wherein R < ¹ > is O and R < ² > is an optionally substituted phenyl group. The phenyl rings represented by ring A and R ² are optionally and independently halogen, lower alkyl, lower halogen alkyl, lower alkoxy, lower halogen alkoxy, CN, NO ₂ , R ⁶ , OR ⁴ , N (R ⁴ ) (R ⁴ ), SR ⁴ , CO ₂ R ⁴ , CON (R ⁴ ) (R ⁴ ), SOR ⁶ , SO ₂ R ⁶ , COR ⁴ , NR ⁴ COR ⁴ , NR ⁴ CON (R ⁴ ) (R _{^{4), SO 2 N (R}} 4) (R 4) and ^NR 4 substituted by one or more groups independently selected from the SOR ^4, compound of claim 18. The compound of Claim 19 represented by the following structural formulas.

(Where R ¹⁰ and R ¹¹ are independently hydrogen, lower alkyl, lower halogen alkyl, furanyl, thienyl, phenyl, lower alkoxy or lower halogen alkoxy groups, and R ³ is independently hydrogen, lower alkyl, Alkyl, lower halogenalkyl, lower alkoxy or lower halogenalkoxy groups.) The phenyl ring represented by R ² is substituted with one or more halogen, lower perfluoroalkyl or lower perfluoroalkoxy groups, and R ¹⁰ and R ¹¹ are independently H, lower alkyl or lower perfluoroalkyl groups. 21. A compound according to claim 20. An effective amount of a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt, solvate or inclusion compound containing it, and a pharmaceutically acceptable carrier or excipient. A pharmaceutical composition comprising:   23. Inflammation of a patient comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt, solvate or inclusion compound comprising it. A method of treating or preventing a disease or immune disease.   A method of inhibiting IL-2 production in a patient comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 21.   A patient's immune response comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt, solvate or inclusion compound comprising it. How to suppress.